JP7347798B2 - Photosensitizer dispersion and its use - Google Patents

Description

The present invention relates to dispersions containing photosensitizers and their uses.

The constant emergence of new multi-resistant bacterial isolates makes treatment of bacterial diseases difficult. Increasingly stringent standards of hygiene and the worldwide spread of nosocomial infections have sparked interest in new pharmaceutical agents, methods and uses that can prevent the spread of multi-resistant pathogens.
Research into alternative treatments to antibiotic therapy has great implications for the treatment of infections caused by bacteria, for example, especially as a result of the identification and increasing occurrence of vancomycin-resistant bacterial strains (VRSA) in Japan and the United States in 2002. have In Europe, the first VRSA patient isolate was obtained in Portugal in 2013.
The increasing resistance of fungal infections to synthetic fungal agents is also exacerbating the problem in the treatment of superficial infections. The clinical consequences of resistance to fungal infection preparations are illustrated by treatment failure, especially in immunosuppressed patients.
New attempts for the eradication of resistant or multiresistant pathogens are therefore, on the one hand, the search for new antagonists, e.g. antibiotics or mitotic inhibitors, and, on the other hand, the search for alternative inactivation possibilities. It is.
As an alternative method, photodynamic inactivation of microorganisms has been demonstrated. Two photooxidation processes play a decisive role in the photodynamic inactivation of microorganisms.
A photosensitizer is excited by light of a predetermined wavelength. Excited photosensitizers cause the production of reactive oxygen species (ROS), on the one hand, radicals such as e.g. superoxide anions, hydrogen peroxide or hydroxyl radicals, and/or on the other hand, e.g. Produces excited molecular oxygen, such as molecular oxygen.
In either reaction, photooxidation of specific biomolecules that are in direct contact with reactive oxygen species (ROS) is important. Here, in particular, oxidation of lipids and proteins, which are present as components of the cell membranes of microorganisms, takes place. Inactivation of the relevant microorganisms is also achieved by destruction of the cell membrane. Similar removal processes are employed for viruses and fungi.
For example, singlet oxygen preferably attacks molecules that are sensitive to oxidation. Oxidation-sensitive molecules are, for example, molecules containing double bonds or oxidation-sensitive groups (phenols, sulfides or thiols). Particularly susceptible to destruction are unsaturated fatty acids, especially in bacterial membranes.
However, many photosensitizers known from the prior art disadvantageously have poorly wettable hydrophobic surfaces.

The aim was therefore to provide compositions containing photosensitizers that ensure easy application and, in particular, at the same time exhibit a hydrophobic surface with good wettability.
Furthermore, the composition comprising the photosensitizer preferably ensures improved adhesion of the photosensitizer after application to the surface.
Furthermore, the effectiveness of the photosensitizer is preferably improved.
However, the composition containing the photosensitizer does not substantially prevent stimulation of the photosensitizer molecules contained in the composition by light of a specific wavelength.

The object of the invention is achieved by providing a dispersion comprising a photosensitizer according to claim 1. The dispersion comprises: (a) at least one photosensitizer; (b) at least one liquid polar phase; and (c) at least one surfactant; and a pressure of 600 to 1200 mbr, preferably consisting of a microemulsion, a gel, or a mixture thereof.

Preferred embodiments of the dispersion according to the invention are specified in claims 1 to 14.

The object of the invention is according to claims 1 to 14 for the inactivation of microorganisms preferably selected from the group consisting of viruses, archaea, bacteria, bacterial spores, protozoa, algae and blood-borne parasites. This is further eliminated by the use of dispersions. This use can be medical or non-medical.

Preferred embodiments of the use according to the invention are specified in dependent claims 16-18.

The object of the present invention is to provide a method for the inactivation of microorganisms preferably selected from the group consisting of viruses, archaea, bacteria, bacterial spores, fungi, fungal spores, protozoa, algae, and blood-borne parasites. It will be further resolved. The method includes the following steps:
(A) contacting a microorganism with a dispersion comprising a photosensitizer according to any one of claims 1 to 14; and (B) applying electromagnetic radiation of a suitable frequency and energy density to said microorganism and said at least one irradiating one photosensitizer.

Preferably, the method according to the invention for the inactivation of microorganisms is carried out in photodynamic therapy of a patient or in photodynamic sterilization of surfaces of objects or spaces or in photodynamic sterilization of liquids. , preferably carried out in photodynamic sterilization of surfaces of objects or photodynamic sterilization of liquids.

The dispersion containing the photosensitizer according to the present invention is
(a) at least one photosensitizer, (b) at least one liquid polar phase, and (c) at least one surfactant; It comprises, preferably consists of, a microemulsion, a gel or a mixture thereof at a pressure of 1200 mbr.

The inventors have found that through the preparation of dispersions containing photosensitizers according to the invention, various different classes of photosensitizers can be applied to even hydrophobic surfaces in an effective manner. ing. By doing so, preferably the amount of photosensitizer required for photodynamic inactivation can be applied to the surface to be treated.

Furthermore, the dispersion according to the invention preferably provides a dispersion comprising a photosensitizer according to the invention and thereby the at least one photosensitizer contained therein, preferably uniformly over the surface to be sterilized. It has sufficient wetting properties even on hydrophobic surfaces for different classes of photosensitizers to be able to be applied and preferably remain attached after application.

After irradiation of the surface to be disinfected with electromagnetic radiation of a suitable wavelength and energy density, preferably in the presence of oxygen and/or an oxygen-donating composition, microorganisms are ensured to be inactivated on the surface to be disinfected. This is preferably ensured.

Furthermore, we have surprisingly found that the dispersion of the invention does not reduce the photodynamic activity of at least one photosensitizer contained therein.

Dispersions containing photosensitizers according to the invention are slightly turbid or not turbid, so that the emitted electron radiation is little or not attenuated at all.

Therefore, the use of at least one photosensitizer in the dispersions of the invention surprisingly results in a higher yield of reactive oxygen species and/or singlet oxygen compared to the use of pure photosensitizer. , surprisingly does not cause a large decrease in .

The highest possible yield of reactive oxygen species or singlet oxygen is desirable for antimicrobial efficiency in photodynamic therapy or photological cleaning of surfaces or liquids.

Stronger turbidity results in a greater energy drop in the emitted electromagnetic radiation. In addition, the occurrence of a countervailing process ("quenching") within the photosensitizer composition allows non-radiative relaxation and/or release of heat to the surroundings to be induced by irradiation with electromagnetic radiation of appropriate wavelength and energy density. Usually, the absorbed energy is released and then channeled through the generation of a fluorescent effect.

This causes a large reduction in photodynamic efficiency (i.e., a reduction in reactive oxygen species (ROS) formed by photodynamic processes and/or excited molecular oxygen formed by photodynamic processes).

In one preferred embodiment of the photosensitizer dispersion according to the invention, the dispersion contains organic compounds containing unsaturated groups (e.g. in the form of double or triple bonds) and oxidizable groups (e.g. Besides the at least one photosensitizer, it does not further contain organic compounds (in the form of thiol and/or aldehyde groups) (these radicals or groups are formed by singlet oxygen or (This is because it reacts with active oxygen species and lowers the quantum yield.)

For example, the photosensitizer dispersion according to the invention may contain, in addition to the at least one photosensitizer, an oxidizable aromatic compound (e.g. phenol, polyphenol, aniline or phenylenediamine) and any other It further contains no activated amino acids (such as histidine or tryptophan) and no imidazoles, alkyl sulfides or thioethers.

Preferably, the photosensitizer dispersions of the present invention are free of fungicides.

In the meaning of the present invention, a "photosensitizer" is a photosensitizer that converts triplet oxygen into reactive oxygen species (ROS) (preferably is understood as a compound that gives rise to free radical oxygen) and/or singlet oxygen.

According to the invention, the concept of "photodynamic therapy" refers to the treatment of cells or microorganisms, in particular viruses, archaea, bacteria, bacterial spores, fungi, fungal spores, protozoa, algae, blood-borne parasites, or combinations thereof. is understood to mean light-induced inactivation of (including) in contact with and/or within the patient.

According to the invention, the term "photodynamic sterilization" refers to microorganisms ( It is understood as a light-inducible inert substance (preferably containing viruses, archaea, bacteria, bacterial spores, fungi, fungal spores, protozoa, algae, blood-borne parasites or combinations thereof).

According to the invention, the term "surface cleaning" is understood as the inactivation of microorganisms on the surface of objects, spaces and/or food products. Here, the microorganisms preferably include viruses, archaea, bacteria, bacterial spores, fungi, fungal spores, protozoa, algae, blood-borne parasites, or combinations thereof. According to the invention, the term "surface purification and/or surface coating" refers to surfaces on the human or animal body (e.g. skin) and/or surfaces within the human or animal body (e.g. the external surface of the epithelium of hollow organs). does not include the apical side).

In the present invention, the concept "inactivation" is understood as the reduction or destruction of the viability of microorganisms, preferably the destruction of microorganisms. Light-induced inactivation can be calculated, for example, on the basis of the reduction in the number of microorganisms after irradiation of a predetermined starting amount of microorganisms in the presence of the dispersion of the invention.

According to the invention, the reduction in viability is at least 80.0%, preferably at least 99.0%, preferably at least 99.9%, more preferably at least 99.99%, even more preferably 99.999%, Even more preferably it is understood that the number of microorganisms is reduced by at least 99.9999%. Very preferably, more than 99.9 and less than 100% of microorganisms are reduced, and more than 99.99 and less than 100% of microorganisms are reduced.

Preferably, the reduction in the number of microorganisms is determined by Boyce, JM and Pittet, D. (“Guidelines for hand hygiene in healthcare settings. Recommendations of the Healthcare Infection Control Practices Advisory Committee and the HIPAC/SHEA/APIC/IDSA Hand Hygiene Task Force ”, Am.J.Infect.Control 30 (8), 2002, Seite 1 - 46), expressed as log ₁₀ -reduction factor.

In the present invention, the concept "log ₁₀ -reduction factor" is defined as the logarithm of the number of microorganisms to the base 10 and the 10 It is understood as the difference between the logarithm of the number of microorganisms and the base value.

Suitable methods for calculating the log ₁₀ -reduction factor are, for example, DIN EN 14885:2007-01 “Chemische Desinfektionsmittel und Antiseptika - Anwendung Europaischer Normen fur chemische Desinfektionsmittel und Antiseptika” or Rabenau, HF and Schwebke, I. (“Leitlinie der Deutschen Vereinigung zur Bekampfung der Viruskrankheiten (DVV) e. 51(8), (2008), 937 - 945).

Preferably, the log ₁₀ -reduction factor is at least 2 log ₁₀ , preferably at least 3 log ₁₀ , more preferably at least 4 log ₁₀ after irradiating the microorganism with electromagnetic radiation in the presence of the dispersion of the invention. , more preferably a log ₁₀ of at least 4.5, even more preferably a log ₁₀ of at least 5, even more preferably a log ₁₀ of at least 6, even more preferably a log ₁₀ of at least 7, even more preferably a log 10 of at least 7.5. It is ₁₀ .

For example, the fact that the number of microorganisms is reduced by two orders of magnitude after irradiation of the microorganisms with electromagnetic radiation in the presence of the dispersion of the present invention means that the number of microorganisms is reduced by a log of 2 for the starting amount of the microorganisms. It is expressed by a log ₁₀ -reduction factor of ₁₀ .

More preferably, the number of microorganisms is increased by at least two orders of magnitude, more preferably at least three orders of magnitude, preferably at least It is subtracted by 4 digits, more preferably by at least 5 digits, even more preferably by at least 6 digits, even more preferably by at least 7 digits.

For the purpose of the present invention, the term "microorganisms" is understood to mean viruses, archaea and prokaryotic microorganisms (such as fungi, protozoa, fungal spores, unicellular algae).

The photosensitizer dispersion according to the invention comprises (a) at least one photosensitizer.

In a preferred embodiment, the at least one photosensitizer is positively charged, negatively charged, uncharged, or a mixture thereof. More preferably, the at least one photosensitizer has a) at least one neutral protonatable nitrogen atom and/or b) at least one positively charged nitrogen atom. Contains one organic group.

In a preferred embodiment, the at least one photosensitizer is selected from the group consisting of phenalenones, curcumins, flavins, porphyrins, porphycenes, xanthene dyes, coumarins, phthalocyanines, phenothiazine compounds, anthracene dyes, pyrenes, fullerenes, perylenes, and mixtures thereof. selected from the group. Said at least one photosensitizer is preferably from the group consisting of phenalenone, curcumin, flavin, porphyrin, phthalocyanine, phenothiazine compounds, and mixtures thereof, more preferably from the group consisting of phenalenone, curcumin, flavin, and mixtures thereof. selected.

Suitable phenalenones are disclosed, for example, in EP 2 678 035 A2, the contents of which are incorporated herein by reference for structures and syntheses of suitable phenalenones.

Preferably, suitable phenalenone derivatives are selected from the group consisting of compounds having formulas (2) to (25), or mixtures thereof:

Preferably, suitable phenalenone derivatives are further selected from the group consisting of compounds having formulas (26) to (28) and mixtures thereof:

More preferably, suitable phenalenone derivatives are selected from the group consisting of compounds having formulas (2) to (28) and mixtures thereof.

Suitable flavins are disclosed in EP 2 723 342 A1, EP 2 723 743 A1 and EP 2 723 742 A1, the contents of which are incorporated herein by reference for structures and syntheses of suitable flavins. has been done.

Preferably, suitable flavin derivatives are selected from the group consisting of compounds with formulas (32) to (49), (51) to (64) and mixtures thereof:

Suitable curcumins are disclosed, for example, in the unpublished patent application EP 18152597.3, the contents of which are incorporated herein by reference for the structure and synthesis of suitable curcumins.

Suitable curcumin derivatives are, for example, selected from the group consisting of compounds having the chemical formulas (75) to (104b), (105) and mixtures thereof:

Suitable curcumin derivatives and their preparation are described, for example, in CA 2 888 140 A1. The contents of which are incorporated herein by reference regarding the structure and synthesis of suitable curcumins.

Suitable curcumin-3,5-dione derivatives and their preparation are also described in EP 2 698 368 A1, the contents of which are incorporated herein by reference with regard to the structure and synthesis of suitable curcumins.

Suitable curcumin derivatives and their preparation are also described in Taka et al. For synthesis, it is incorporated herein.

Suitable commercially available phenothiazinium dyes are, for example, new methylene blue (NMB, 3,7-bis(ethylamino)-2,8-dimethylphenothiazin-5-ium chloride), 1,9-dimethyl-methylene blue (DMMB, 3,7-bis-(dimethylamino)-1,9-dimethyl-diphenothiazin-5-ium-zinc chloride), or methyl green (basic green, 5,[7-(dimethylamino)-4-nitrophenothiazine- 3-ylidene] -dimethylazanium chloride).

Suitable commercially available polymethine dyes are, for example, cyanine-5 (Cy5), cyanine-3 (Cy3), or indocyanine green (ICG).

Suitable commercially available xanthine dyes are, for example, pyronin G, eosin B, eosin Y, rose bengal erythrosin (E127), or phloxine B.

Suitable commercially available triphenylmethane dyes include, for example:
Patent Blue V (4-[4,4'-bis(diethylamino)-α-hydroxy-benzhydryl]-6-hydroxy-benzole-1,3-disulfonic acid), Malachite Green (N,N,N',N'-tetramethyl-4,4'-diaminotriphenylcarbenium chloride), fuchsin (4-[(4-aminophenyl)-(4-imino-1-cyclohexa-2,5-dienylidene)methyl]aniline hydrochloride) , parafuchsin (4,4'-(4-iminocyclohexa-2,5-dienylidene methylene)dianiline hydrochloride), crystal violet ((4-(4,4'-bis(dimethylaminophenyl)benzhydrylidene)cyclohexa -2,5-dien-1-ylidene)dimethylammonium chloride).

Suitable commercially available anthraquinone dyes are, for example, (1,2-dihydroxyanthraquinone) or indanthreen (6,15-dihydro-5,9,14,18-anthracentetrone).

Suitable commercially available porphyrin dyes are, for example, 5,10,15,20-tetrakis(1-methyl-4-pyridinio)porphyrin-tetra(p-toluenesulfonate) (TMPyP), or tetrakis(p-trimethylammoniumphenyl). It is a porphyrin chloride.

Suitable commercially available phthalocyanine dyes are, for example, zinc phthalocyanine tetrasulfonate or tetrakis(p-trimethylammonium)phthalocyanine zinc chloride.

Suitable commercially available indamine dyes are, for example, Safranin T (3,7-diamino-2,8-dimethyl-5-phenylphenazinium chloride), or Phenosafranine (3,7-diamino-5-phenylphenazinium chloride).

The above dyes are sold by, for example, AppliChem GmbH (Darmstadt, DE), Frontier Scientific Inc. (Logan, UT), GE Healthcare Europe GmbH (Freiburg, DE), and Sigma-Aldrich Corporation (St. Louis, MO, USA). , or Merck KGaA (Darmstadt, DE).

Any suitable anion can be used as a counterion to the positively charged nitrogen atom. The counter ions for the positively charged nitrogen atoms are preferably fluoride, chloride, bromide, iodide, sulfate, hydrogen sulfate, phosphate, dihydrogen phosphate, hydrogen phosphate. , tosylate, mesylate, formate, acetate, propionate, butanoate, oxalate, tartrate, fumarate, benzoate, citrate, and/or mixtures thereof. It is an anion selected from the group.

Preferably, the at least one photosensitizer has a formula (2) to (25), a formula (32) to (49), a formula (51) to (64), a formula (75) to 105), and mixtures thereof.

Preferably, said dispersion comprises said at least one photosensitizer at a concentration ranging from 0.1 to 1000 μM.

The dispersion according to the invention further comprises (b) at least one liquid polar phase.

Preferably, said at least one liquid polar phase exists in liquid state at a temperature in the range from 0°C to 100°C and a pressure in the range from 800 to 1200 mbar.

Preferably, said at least one liquid polar phase comprises at least one polar solvent, preferably water.

Preferably, the dispersion of the invention contains at least one polar solvent (preferably water), based on the total weight of the dispersion, at least 0.1 wt%, preferably at least 0.5 wt%, more preferably at least 1 wt%, more preferably at least 4 wt%, more preferably at least 10 wt%, more preferably at least 35 wt%, more preferably at least 50 wt%, more preferably at least 51 wt%.

Preferably, the dispersion of the invention contains at least one polar solvent (preferably water) in the range of 0.1 wt% to 99.8 wt%, preferably 0.5 wt%, relative to the total weight of the dispersion. to 99 wt%, more preferably 4 wt% to 98 wt%, more preferably 10 wt% to 97 wt%, more preferably 35 wt% to 96 wt%, more preferably 50 wt% to 95 wt%, More preferably, it is contained in a proportion ranging from 51 wt% to 94 wt%, more preferably from 53 wt% to 93 wt%, and even more preferably from 70 wt% to 92 wt%.

The dispersion of the invention further comprises (c) at least one surfactant.

Preferably, the dispersion of the present invention contains at least one surfactant in the range of 0.1 wt% to 65 wt%, preferably in the range of 1 wt% to 55 wt%, more preferably in the range of 1 wt% to 55 wt%, relative to the total weight of the dispersion. ranges from 3 wt% to 50 wt%, more preferably from 5 wt% to 41 wt%, more preferably from 7 wt% to 37 wt%, more preferably from 9 wt% to 30 wt%, more preferably from 10 wt% to 27 wt%. Included in proportions selected from the range.

Preferably, the at least one surfactant is a nonionic surfactant, an anionic surfactant, a cationic surfactant, an amphoteric surfactant and mixtures thereof, preferably a nonionic surfactant, an anionic surfactant. surfactants and mixtures thereof.

Said at least one surfactant preferably has an HLB value in the range from 4 to 40, preferably in the range from 5 to 20. The HLB value of a surfactant can be determined by, for example, Griffin, W.C. (1949) ("Classification of Surface-Active Agents by 'HLB'", J. Soc. Cosmet. Chem. 1 (5), pages 311 to 326) or Griffin , W.C. (1954) ("Calculation of HLB Values of non-Ionic Surfactants", J. Soc. Cosmet. Chem. 5 (4): pages 249 to 256).

Preferably, suitable nonionic surfactants are selected from the group consisting of polyalkylene glycol ethers, alkyl polyglycosides, alkyl glycosides, and mixtures thereof.

Suitable polyalkylene glycol ethers preferably have the general formula (I).
CH ₃ -(CH ₂ ) _m -(O-[CH ₂ ] _x ) _n -OH, (I)
where m = 8 to 20, preferably 10 to 16, n = 1 to 25, x = 1, 2, 3 or 4.

Preferably, a combination of different polyalkylene glycol ethers is used. For example, a combination of different polyalkylene glycol ethers with different alkoxy units (-(O-[CH ₂ ] _x ) _n -) is used.

Suitable polyalkylene glycol ethers are, for example, polyoxyethylene ethers of lauryl alcohol (dodecane-1-ol), polyoxyethylene ethers of cetyl alcohol (hexadecane-1-ol), polyoxyethylene ethers of stearyl alcohol (1-octadecanol), etc. Polyoxyethylene ether, polyoxyethylene ether of oleyl alcohol ((E)-octadec-9-en-1-ol), or polyoxyethylene ether of a mixture of stearyl alcohol and cetyl alcohol (cetylstearyl alcohol).

Suitable polyalkylene glycol ethers are commercially available, for example, under the trade names Brij, Thesit, Cremophor, Genapol, Magrogol, Lutensol, etc.

Suitable polyalkylene glycol ethers include, for example:

Suitable alkyl glucosides are, for example, ethoxylated sorbitan fatty acid esters (polysorbates), which are commercially available, for example, under the trade name Tween® from Croda International Plc (Snaith, UK).

Other suitable alkyl glucosides are, for example, the surfactant Kosteran SQ/O VH. It is commercially available from Dr. W. Kolb AG (Hedingen, CH). Kosteran SQ/O VH is sorbitan oleate (sorbitan sesquioleate) with an average of 1.5 oleic acid molecules per molecule.

Other suitable alkyl glucosides are, for example, PEG-80 sorbitan laurate. This is an ethoxylated sorbitan monoester of lauric acid with an average ethylene oxide content of 80 Mol per molecule. PEG-80 sorbitan laurate is commercially available, for example, from Croda International Plc. under the trade name Tween(R) 28.

Suitable alkyl glucoside esters are fatty acid esters of methyl glucoside or ethyl glucoside, for example methyl glucoside ester, ethyl glucoside ester or sucrose ester.

Preferably, suitable anionic surfactants are alkyl carboxylates, alkyl sulfonates, alkyl sulfates, alkyl phosharts, alkyl polyglycol ether sulfates, sulfonates of alkyl carboxylic acids, N-alkyl sarcosinates, and mixtures thereof.

Suitable alkyl carboxylates preferably have the general formula (II).
H ₃ C-(CH ₃ ) _a -CH ₂ -COO ^- M ⁺ , (II)
where a = 5 to 21, preferably 8 to 16, and M ⁺ is a water-soluble cation, preferably an alkali metal or ammonium cation, preferably Li ⁺ , Na ⁺ , K ⁺ or NH It is ₄ ⁺ .

Suitable alkyl sulfonates preferably have 3 to 30 carbon atoms. Suitable alkyl sulfonates are preferably monoalkyl sulfonates having 8 to 20 C atoms, secondary alkyl sulfonates of general formula (III).

式中、ｘとｙはそれぞれ独立して、０～１７であり、好ましくはｘ＋ｙは１０～２０であり、M⁺は水溶性カチオンであり、好ましくはアルカリ金属またはアンモニウムのカチオンであり、好ましくはＬｉ^＋、Ｎａ^＋、Ｋ^＋、またはＮＨ４^＋である。

where x and y are each independently from 0 to 17, preferably x + y is from 10 to 20, and M ⁺ is a water-soluble cation, preferably an alkali metal or ammonium cation, preferably Li ⁺ , Na ⁺ , K ⁺ , or NH4 ⁺ .

Suitable alkyl sulfonates preferably have the general formula (IV).
H ₃ C-(CH ₃ ) _d -CH ₂ -O-SO ₃ ^- M ⁺ , (IV)
where d = 6 to 20, preferably 8 to 18, and M ⁺ is a water-soluble cation, preferably an alkali metal or ammonium cation, preferably Li ⁺ , Na ⁺ , K ⁺ or NH4 ⁺ be.

A suitable alkyl sulfate is, for example, sodium dodecyl sulfate (SDS).

Suitable alkyl phosphates preferably have the general formula (V).
H ₃ C-(CH ₃ ) _e -CH ₂ -O-PO ₃ ^2- 2 x M ⁺ , (V)
where e = 6 to 20, preferably 8 to 18, and M ⁺ is a water-soluble cation, preferably an alkali metal or ammonium cation, preferably Li ⁺ , Na ⁺ , K ⁺ or NH4 ⁺ be.

Suitable alkyl polyglycol ether sulfates preferably have 6 to 22 carbon atoms, preferably 8 to 20 carbon atoms and 1 to 10 ethylene oxide units, preferably 2 to 6 carbon atoms. Contains an ethylene oxide unit in the ether moiety.

A suitable N-alkyl sarcosinate is N-lauroyl sarcosinate.

Suitable alkyl carboxylate sulfonates preferably contain 6 to 30 carbon atoms, preferably 8 to 20 carbon atoms.

Preferably, suitable alkyl carboxylate sulfonates contain at least one alkyl group having 6 to 20 carbon atoms, preferably 8 to 18 carbon atoms and 2 to 10 carbon atoms, preferably contains an alkyl carboxylate group having 2 to 6 carbon atoms. The alkyl groups may include polyoxyethylene (POE) groups.

Suitable alkyl carboxylate sulfonates are, for example, monoalkyl ester sulfosuccinates or dialkyl ester sulfosuccinates (eg dioctyl sodium sulfosuccinate).

Preferably, suitable cationic surfactants are quaternary alkyl ammonium salts, esterquats, acrylated polyamines, benzyl ammonium salts, or mixtures thereof.

Suitable alkylammonium salts preferably have the general formula (VI).
(R ¹ )(R ² )(R ³ )(R ⁴ )N ⁺ Z ^- (VI)
In the formula, the organic radical R ¹ denotes an alkyl group, which may be linear or branched, preferably linear, and having from 8 to 20 carbon atoms, preferably from 10 to having 18 carbon atoms, more preferably 12 to 16 carbon atoms, and the organic radicals R ² , R ³ and R ⁴ each independently mean an alkyl radical, where the alkyl radical is linear or may be branched, preferably linear, having 1 to 20 carbon atoms, preferably 1 to 16 carbon atoms, more preferably 1 to 12 C atoms; Z means an anion, preferably fluoride, chloride, bromide, iodide, sulfate, hydrogen sulfate, phosphate, dihydrogen phosphate, hydrogen phosphate, tosylate. , mesylate, formate, acetate, propionate, butanoate, oxalate, tartrate, fumarate, benzoate, citrate and/or mixtures thereof. .

Preferably, the organic radical R ¹ is the group consisting of octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosadecyl, and combinations thereof, preferably dodecyl, tridecyl, tetradecyl , pentadecyl, hexadecyl, and combinations thereof.

Preferably, the organic radicals ^R2 , ^R3 , and ^R4 are each independently methyl, ethyl, propyl, butyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, An alkyl radical selected from the group consisting of nonadecyl, eicosadecyl, and combinations thereof, preferably methyl, ethyl, propyl, butyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, and combinations thereof.

For example, suitable alkylammonium salts of general formula (VI) are monoalkyltrimethylammonium salts of the anion, preferably fluoride, chloride, bromide, iodide, sulfate, hydrogen sulfate, phosphate, Dihydrogen phosphate, hydrogen phosphate, tosylate, mesylate, formate, acetate, propionate, butanoate, oxalate, tartrate, fumarate, benzoate, citric acid selected from the group consisting of salts and/or mixtures thereof, wherein the organic radical R ¹ is octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosadecyl, and combinations thereof. preferably selected from the group consisting of dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, and combinations thereof, and the organic radicals R ² , R ³ and R ⁴ each mean methyl.

For example, suitable alkylammonium salts of general formula (VI) are anionic dialkyltrimethylammonium salts, preferably fluoride, chloride, bromide, iodide, sulfate, hydrogen sulfate, phosphate, di- Hydrogen phosphate, hydrogen phosphate, tosylate, mesylate, formate, acetate, propionate, butanoate, oxalate, tartrate, fumarate, benzoate, citrate and/or mixtures thereof, and the organic radicals R ¹ and R ² are selected from the group consisting of octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosadecyl, and , preferably dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, and combinations thereof, and the organic radicals R ³ and R ⁴ each represent methyl. means.

Suitable alkylammonium salts of general formula (VI) are preferably dodecyltrimethylammonium bromide (DTAB) and/or didodecyldimethylammonium bromide (DDAB).

Suitable esterquats include, for example, triethanolamine-diesterquat, diethanolmethylamine-diesterquat, or mixtures thereof.

Suitable esterquats are, for example, based on triethanolamine or diethanolmethylamine, e.g. diethanolmethylamine esterified with one or two molecules of fatty acid, or in the case of triethanolamine one, two or three molecules. It can be prepared by esterification with a fatty acid, preferably two molecules of fatty acid, followed by quaternization with methyl chloride, methyl bromide, or dimethyl sulfate. As fatty acids, fatty acids having 8 to 24 carbon atoms (saturated or unsaturated) are used for the esterification.

Preferably, suitable amphoteric surfactants contain both negatively charged and positively charged functional groups. Suitable amphoteric surfactants are, for example, alkylbetaines of alkyl radicals with 8 to 20 C atoms, alkylsulfobetaines of alkyl radicals with 8 to 20 carbon atoms, lectins, or combinations thereof. be.

Suitable amphoteric surfactants are, for example, CHAPS (3-[(3-cholamidopropyl)dimethylammonio]-1 propanesulfonate), CHAPSO (3-[(3-cholamidopropyl)dimethylammonio]- 2-hydroxy-1-propanesulfonate), cocamidopropylhydroxysultaine, 1,2 di-n-octanoyl-sn-glycero-3-phosphocholine, 1,2-di-O-hexadecyl-sn-glycero-3 - Phosphocholine, or cocamidopropyl betaine.

The dispersion of the invention preferably further comprises at least one alkanol having 2 to 12 carbon atoms and at least one OH group, preferably 1 to 6 OH groups.

Preferably, the dispersion of the present invention contains the at least one alkanol in the range of 0 wt% to 50 wt%, preferably in the range of 0.1 wt% to 40 wt%, more preferably in the range of 0.1 wt% to 40 wt%, relative to the total weight of the dispersion. In the range of 0.5 wt% to 35 wt%, more preferably in the range of 1 wt% to 30 wt%, more preferably in the range of 1.5 wt% to 25 wt%, more preferably in the range of 5 wt% to 20 wt%, more preferably 7 wt%. and 19 wt%, more preferably 10 wt% to 17 wt%.

Preferably, said at least one alkanol having from 2 to 12 carbon atoms is used as a co-surfactant when at least one anionic, cationic or amphoteric surfactant is used. It will be done.

Suitable alkanols have 2 to 12 carbon atoms and at least one OH group, preferably 1 to 6 OH groups, preferably 1 to 3 OH groups, or mixtures thereof. , branched or unbranched, preferably unbranched, alkanol.

Preferably, suitable alkanols are branched or unbranched and have 2 to 12 carbon atoms, more preferably 4 to 10 carbon atoms.

Suitable alkanols with one OH group are preferably ethanol, 1-propanol, 2-propanol, 1-butanol, 2-methyl-2-propanol, 1 pentanol, 3-methyl-1-butanol, 1 -hexanol, 1-heptanol, 1-octanol, 1-nonanol, 1-decanol, 1-undecanol, 1-dodecanol, and mixtures thereof.

Suitable unbranched alkanols having more than one OH group, preferably 2 or 3 OH groups are preferably propane-1,2-diol (propylene glycol), propane-1,3-diol, Butane-1,2 diol, butane-1,3-diol, butane-1,4-diol, butane-2,3-diol, pentane-1,5-diol, octane-1,8-diol, propane-1 , 2,3 triols (glycerin) or mixtures thereof.

Preferably, the mass ratio of surfactant to alkanol is from 4:1 to 1:4, preferably from 3:1 to 1:3, preferably from 2:1 to 1:2, more preferably 1:1. .

In the dispersion of the present invention, preferably certain constituents of the dispersion of the present invention are finely dispersed within the other continuous constituents of the dispersion of the present invention (dispersion medium, coherent phase). (dispersed phase).

Preferably, the dispersion of the invention is a thermodynamically stable dispersion at a temperature in the range from 2 to 50°C and a pressure in the range from 800 to 1200 mbar, the dispersion comprising at least one liquid phase. preferably with little separation, more preferably without separation.

Preferably, the dispersion of the invention comprises or is a microemulsion, a gel (preferably a lyogel), or a mixture thereof, preferably a microemulsion and/or a lyogel.

The inventors have proposed that the dispersion of the invention, which comprises or is a microemulsion, a gel (preferably a lyogel), or a mixture thereof, can be prepared at a temperature in the range from 2 to 50 °C and in the range from 800 to 1200 mbar. It has been found that at a pressure of 1 to 5 years, there is little separation, more preferably no separation, preferably for a period of 1 to 5 years.

In an alternative embodiment, the dispersion of the invention comprises or is a microemulsion itself, at a pressure selected from the range 800 to 1200 mbar and a temperature range from 2 to 50°C; , preferably of a size less than 1 μm, preferably less than 350 nm, preferably less than 100 nm, more preferably in the range from 1 nm to 95 nm (inclusive), more preferably in the range from 5 nm to 50 nm (inclusive) with drops.

Preferably, in the microemulsion, the dispersed phase is a liquid phase, and the liquid phase is dispersed in another liquid phase (dispersion medium), and the at least one photosensitizer is preferably in the dispersed phase, Dissolved in the dispersion medium or both phases.

The microemulsion of the invention preferably further comprises at least one liquid non-polar phase. Preferably, said at least one liquid non-polar phase is in a liquid state at a temperature in the range from 0°C to 100°C and a pressure from 800 to 1200 mbar.

Preferably, said at least one liquid non-polar phase comprises at least one non-polar solvent, preferably an aprotic non-polar solvent.

Preferably, the microemulsion of the invention comprises at least 0.1 wt%, preferably at least 0.5 wt%, more preferably at least 1 wt% of the at least one non-polar solvent, based on the total weight of the microemulsion. More preferably at least 4 wt%, more preferably at least 10 wt%, more preferably at least 35 wt%, more preferably at least 50 wt%, more preferably at least 51 wt%.

Preferably, the microemulsion of the present invention contains the at least one non-polar solvent in a range of 0.1 wt% to 99.8 wt%, preferably 0.5 wt% to 99 wt%, based on the total weight of the macroemulsion. more preferably in the range of 1 wt% to 96 wt%, more preferably in the range of 1.5 wt% to 90 wt%, more preferably in the range of 3 wt% to 80 wt%, more preferably in the range of 5 wt% to 75 wt%. It is preferably contained in a proportion ranging from 10 wt% to 60 wt%, more preferably from 12 wt% to 49 wt%.

Preferably, the at least one non-polar solvent is an alkane having 6 to 30 carbon atoms, a monocarboxylic acid ester having 4 to 20 carbon atoms, a polycarboxylic acid ester having 6 to 20 carbon atoms. selected from the group consisting of carboxylic acid esters, and mixtures thereof.

Preferably, the alkanes, monocarboxylic esters and polycarboxylic esters described above are dissolved in the at least one polar solvent (preferably water) at a temperature ranging from 2 to 50°C and a pressure ranging from 800 to 1200 mbr. The solubility is less than 1 g per liter of polar solvent (preferably water). More preferably, the alkanes, monocarboxylic esters and polycarboxylic esters mentioned above are not soluble in polar solvents (preferably water) at temperatures ranging from 10 to 25°C and pressures ranging from 800 to 1200 mbr.

Preferably, suitable alkanes, monocarboxylic esters and polycarboxylic esters have boiling points (bp) above 80°C, preferably above 100°C. Preferably, the alkanes, monocarboxylic esters and polycarboxylic esters have melting points (mp) below 20°C, preferably below 10°C, more preferably below 0°C.

Suitable alkanes are straight-chain or branched and acyclic, having from 5 to 30 carbon atoms, preferably from 6 to 25 carbon atoms, more preferably from 8 to 20 carbon atoms. Preference is given to alkanes or cyclic alkanes having 5 to 13 carbon atoms, more preferably 6 to 12 carbon atoms, or mixtures thereof.

Suitable alkanes may be unsubstituted or substituted with fluorine atoms. Preferably, suitable fluorinated alkanes are perfluoroalkanes having 5 to 20 carbon atoms, such as perfluoroheptane, perfluorooctane, perfluorononane, perfluorodecane, perfluorodecalin, or mixtures thereof.

Suitable cyclic alkanes are preferably cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cycloundecane or mixtures thereof.

Suitable cyclic alkanes are cyclic alkyl radicals having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, tert-butyl, n- May be further substituted with pentyl or combinations thereof, for example ethylcyclopentane, propylcyclopentane, n-butylcyclopentane, sec-butylcyclopentane, tert-butylcyclopentane, n-pentylcyclopentane, methylcyclohexane, ethyl selected from the group consisting of cyclohexane, propylcyclohexane, n-butylcyclohexane, sec-butylcyclohexane, tert-butylcyclohexane, n-pentylcyclohexane, or mixtures thereof.

Suitable acyclic alkanes are more preferably mixtures of liquid acyclic alkanes and have a melting point (mp) below 20°C.

A suitable mixture of alkanes is preferably paraffin oil, more preferably white oil. Suitable white oils are, for example, medicinal white oils.

Suitable liquid paraffins are, for example, on the CAS list with number CAS-8012-95-1 or on the EINECS list with number EG 232-384-2. Their concentration is preferably between 0.81 and 0.89 g/cm ³ . More preferably, suitable liquid paraffins have boiling points above 250°C.

Preferably, suitable monocarboxylic acid esters are esters of alkanols, preferably having from 1 to 10 carbon atoms, and alkane monocarboxylic acids, preferably having from 2 to 16 carbon atoms; The carboxylic ester preferably has 4 to 20 carbon atoms.

Preferably, said polycarboxylic acid ester having 6 to 20 carbon atoms has 2 to 4 carboxy groups, which carboxy groups are preferably fully esterified.

Suitable polycarboxylic esters are preferably diesters of alkanedicarboxylic acids having 4 to 8 carbon atoms and alkanols having 1 to 12 carbon atoms. Preferably, the alkanedicarboxylic acid may be substituted with an OH group.

Suitable polycarboxylic acid esters are, for example, dimethyl succinate, diethyl succinate, dimethyl sebacate, diethyl sebacate, diethylhexyl adipate, diisononyl adipate, dimethyl tartrate, diethyl tartrate, diisopropyl tartrate, or mixtures thereof. .

Unless stated otherwise, chiral centers can exist in the S or R configuration. The present invention relates to the use of optically pure compounds and stereoisomeric mixtures, such as enantiomeric and diastereomeric mixtures, in all proportions.

For example, diethyl tartrate may be present as (2S,3S)-diethyl tartrate, (2R,3R)-diethyl tartrate, (2R,3S)-diethyl tartrate, or mixtures thereof.

Preferably, the microemulsion is a thermodynamically stable emulsion at temperatures in the range from 2 to 50°C and pressures in the range from 800 to 1200 mbar, the dispersed phase forming very small areas ("droplets"). Therefore, visible light is not scattered in this region. Preferably, the microemulsions of the invention are transparent.

Preferably, the microemulsion of the invention is an oil-in-water (O/W) microemulsion, a water-in-oil (W/O) microemulsion, or a bicontinuous microemulsion, preferably an oil-in-water ( O/W) microemulsion or water-in-oil (W/O) microemulsion)
(a) at least one photosensitizer, the above phenalenone, the above curcumin, the above flavin, the above porphyrin, the above porphycene, the above xanthine pigment, the above coumarin, the above phthalocyanine, the above phenothiazine; More preferably, the compound is selected from the group consisting of an anthracene dye as described above, a pyrene as described above, a fullerene as described above, a perylene as described above, and mixtures thereof, as described above, a phenalenone as described above, a curcumin as described above, a flavin as described above, a porphyrin as described above. , the above-mentioned phthalocyanines, the above-mentioned phenothiazine compounds, and mixtures thereof, and the above-mentioned phenalenones, the above-mentioned curcumins, the above-mentioned flavins, and mixtures thereof. More preferably, it consists of compounds of formula (2) to formula (28), formula (32) to formula (49), formula (51) to formula (64), formula (75) to formula (105), and mixtures thereof. at least one photosensitizer, more preferably selected from the group;
(b) at least one polar solvent (preferably water);
(c) at least one surfactant consisting of a nonionic surfactant as described above, an anionic surfactant as described above, a cationic surfactant as described above, an amphoteric surfactant as described above, and mixtures thereof. at least one surfactant selected from the group consisting of the above-mentioned nonionic surfactants, the above-mentioned anionic surfactants and mixtures thereof;
(d) at least one non-polar solvent, an acyclic alkane having 5 to 30 carbon atoms as defined above, a cyclic alkane having 5 to 13 carbon atoms as defined above, 5 as defined above; perfluoroalkanes having 20 carbon atoms from, monocarboxylic esters having 4 to 20 carbon atoms as described above, polycarboxylic esters having 6 to 20 carbon atoms as described above, and mixtures thereof. at least one non-polar solvent, more preferably selected from the group consisting of:

Preferably, the microemulsion of the invention comprises:
(e) further comprising at least one alkanol selected from the group consisting of alkanols having 2 to 12 carbon atoms and preferably 1 to 6 OH groups as defined above, and mixtures thereof.

Preferably, said at least one surfactant is selected from the group consisting of anionic surfactants as described above and mixtures thereof; further comprises at least one alkanol selected from the group consisting of alkanols having 1 to 6 OH groups, and mixtures thereof.

Preferably, the microemulsion of the invention may comprise or consist of an oil-in-water (O/W) microemulsion, a water-in-oil (W/O) microemulsion, or a bicontinuous microemulsion, preferably: It may comprise or consist of an oil-in-water (O/W) microemulsion or a water-in-oil (W/O) microemulsion.

The bicontinuous microemulsion preferably comprises two regions, a hydrophobic region and a hydrophilic region, in the form of extended, adjacent, intertwined regions, the boundary between which is a monolayer of stabilizing surfactants. It is fortified with an agent.

The microemulsion of the invention may, in an alternative embodiment, comprise or consist of an oil-in-water (O/W) microemulsion, wherein the dispersed phase comprises at least one liquid non-polar phase, and the at least one liquid The nonpolar phase is an alkane having 6 to 30 carbon atoms as described above, a monocarboxylic acid ester having 4 to 20 carbon atoms as described above, or a polycarboxylic acid having 6 to 20 carbon atoms as described above. More preferably, it includes at least one non-polar solvent selected from the group consisting of acid esters, and mixtures thereof. Preferably, the dispersion medium of the oil-in-water (O/W) microemulsion comprises at least one polar solvent, preferably water.

Preferably, the oil-in-water (O/W) microemulsion of the present invention contains at least one non-polar solvent in the range of 0.1 wt% to 49.9 wt%, preferably based on the total weight of the microemulsion. In the range of 0.5 wt% to 48 wt%, more preferably in the range of 1 wt% to 45 wt%, more preferably in the range of 3 wt% to 40 wt%, more preferably in the range of 5 wt% to 35 wt%, more preferably in the range of 7 wt% to 30 wt%. Contains in proportions in the range of %.

Preferably, the oil-in-water (O/W) microemulsion of the present invention contains the at least one polar solvent (preferably water) in an amount ranging from 50 wt% to 99.8 wt%, based on the total weight of the microemulsion. , preferably in the range of 51 wt% to 99 wt%, more preferably in the range of 52 wt% to 96 wt%, more preferably in the range of 53 wt% to 90 wt%, more preferably in the range of 54 wt% to 85 wt%.

Preferably, the oil-in-water (O/W) microemulsion of the present invention contains the at least one surfactant in an amount ranging from 0.1 wt% to 45 wt%, preferably 0. .5 wt% to 40 wt%, more preferably 1 wt% to 35 wt%, more preferably 3 wt% to 30 wt%, more preferably 5 wt% to 27 wt%, more preferably 7 wt% to 25 wt%. , more preferably in a range of 10 wt% to 20 wt%.

Preferably, the oil-in-water (O/W) microemulsion of the present invention contains the at least one alkanol in the range of 0 wt% to 50 wt%, preferably from 0.1 wt%, based on the total weight of the microemulsion. In the range of 40 wt%, more preferably in the range of 0.5 wt% to 35 wt%, more preferably in the range of 1 wt% to 30 wt%, more preferably in the range of 1.5 wt% to 25 wt%, more preferably in the range of 5 wt% to 20 wt%. , more preferably in the range of 7 wt% to 19 wt%, more preferably in the range of 10 wt% to 17 wt%.

The microemulsion of the invention may, in a further alternative embodiment, comprise or consist of a water-in-oil (W/O) microemulsion, the dispersed phase comprising at least one polar solvent, preferably water. . Preferably, the dispersion medium of the water-in-oil (W/O) microemulsion comprises a non-polar phase, more preferably the non-polar phase is a non-cyclic phase having from 5 to 30 carbon atoms as described above. alkanes of the formula, cyclic alkanes with 5 to 13 carbon atoms as described above, perfluoroalkane with 5 to 20 carbon atoms as described above, monocarboxylic acid esters with 4 to 20 carbon atoms as described above , polycarboxylic acid esters having 6 to 20 carbon atoms as described above, and mixtures thereof.

Preferably, the water-in-oil (W/O) microemulsion of the present invention contains at least one polar solvent (preferably water) in an amount of 0.1 wt% to 49.9 wt%, based on the total weight of the microemulsion. preferably in the range of 0.5 wt% to 48 wt%, more preferably in the range of 1 wt% to 45 wt%, more preferably in the range of 3 wt% to 40 wt%, more preferably in the range of 5 wt% to 35 wt%, more preferably in the range of 5 wt% to 35 wt%. is contained in a proportion ranging from 7wt% to 30wt%.

Preferably, the water-in-oil (W/O) microemulsion of the present invention contains the at least one non-polar solvent in a range of 50 wt% to 99.8 wt%, preferably based on the total weight of the microemulsion. It further comprises in a proportion ranging from 51 wt% to 99 wt%, more preferably from 52 wt% to 96 wt%, more preferably from 55 wt% to 90 wt%, more preferably from 60 wt% to 80 wt%.

Preferably, the water-in-oil (W/O) microemulsion of the present invention comprises the at least one surfactant and the at least one alkanol in the above-mentioned weight ratio relative to the total weight of the microemulsion. Including further.

Preferably, the water-in-oil (W/O) microemulsions of the invention or the oil-in-water (O/W) microemulsions of the invention contain metals present in the at least one polar solvent (preferably water). The oil of the present invention The water-in-water (W/O) microemulsion or the oil-in-water (O/W) microemulsion of the present invention contains fluoride, chloride, bromide, iodide, sulfate, hydrogen sulfate, phosphate, dihydrogen. Phosphate, hydrogen phosphate, tosylate, mesylate, formate, acetate, propionate, butanoate butanoate, oxalate, tartrate, fumarate, benzoate, citric acid selected from the group consisting of acid salts and/or mixtures thereof, more preferably from the group consisting of chlorides, sulphates, hydrogen sulphates, formates, acetates, benzoates, citrates, and/or mixtures thereof further comprising at least one anion.

Preferably, the water-in-oil (W/O) microemulsion of the invention or the oil-in-water (O/W) microemulsion of the invention contains at least one soluble salt, relative to the total weight of the microemulsion. , in the range of 0 wt% to 20 wt%, preferably in the range of 0.5 wt% to 15 wt%, more preferably in the range of 0.7 wt% to 10 wt%, more preferably in the range of 1 wt% to 7 wt%, more preferably 1. It is included in proportions ranging from 5 wt% to 5 wt%.

Preferably, the microemulsions of the invention are single-phase, thermodynamically stable, more preferably at temperatures in the range from 2 to 50°C and pressures in the range from 800 to 1200 mbar.

More preferably, the microemulsion has a size of less than 350 nm, preferably less than 100 nm, more preferably a size of 1 nm to 95 nm, more preferably a size of 5 nm to 50 nm, including 50 nm. Contains droplets of.

The inventors have surprisingly found that by providing at least one photosensitizer in the microemulsion, the at least one photosensitizer preferably being dissolved in the microemulsion, the It has been found that the applicability of photosensitizers is improved.

For example, the at least one photosensitizer can be provided in a concentrated solution containing a higher concentration of photosensitizer than is required in the application solution, for example.

Preferably, the concentrate is also present in the form of a microemulsion. The inventors have surprisingly found that the microemulsion of the present invention can be prepared by adding several times the amount of water, preferably from 4 to 16 times the amount of water to the amount of concentrate to be diluted. It has been found that the resulting diluted solution can be diluted without significantly reducing its wettability compared to the wettability of the concentrated solution.

In an alternative embodiment, the dispersion of the invention comprises or is a gel, preferably a lyogel, at a pressure in the range from 800 to 1200 mbar and a temperature in the range from 2 to 50°C.

Preferably, the dispersed phase in a gel (preferably a lyogel) is a solid element dispersed in a liquid phase (dispersion medium). Preferably, said at least one photosensitizer is dissolved in said liquid phase.

Preferably, in this case the solid element constitutes a spongy three-dimensional network, the pores of which are filled with liquid (lyogel). Thereby, the liquid element is preferably immobilized in the solid element. At the same time, both elements penetrate each other, preferably completely (bicoherence).

Preferably, the gel (preferably lyogel) of the invention comprises:
(a) at least one photosensitizer, the above phenalenone, the above curcumin, the above flavin, the above porphyrin, the above porphycene, the above xanthine pigment, the above coumarin, the above phthalocyanine, the above phenothiazine; More preferably, the compound is selected from the group consisting of an anthracene dye as described above, a pyrene as described above, a fullerene as described above, a perylene as described above, and mixtures thereof, as described above, a phenalenone as described above, a curcumin as described above, a flavin as described above, a porphyrin as described above. , the above-mentioned phthalocyanines, the above-mentioned phenothiazine compounds, and mixtures thereof, and the above-mentioned phenalenones, the above-mentioned curcumins, the above-mentioned flavins, and mixtures thereof. More preferably, it consists of compounds of formula (2) to formula (25), formula (32) to formula (49), formula (51) to formula (64), formula (75) to formula (105), and mixtures thereof. at least one photosensitizer, more preferably selected from the group;
(b) at least one polar solvent (preferably water);
(c) at least one surfactant consisting of a nonionic surfactant as described above, an anionic surfactant as described above, a cationic surfactant as described above, an amphoteric surfactant as described above, and mixtures thereof. at least one surfactant selected from the group consisting of the above-mentioned nonionic surfactants, the above-mentioned anionic surfactants and mixtures thereof;
(d) at least one gelling agent.

Suitable gelling agents are preferably selected from the group consisting of polyacrylic acids, polyacrylamides, alginates, cellulose ethers, and mixtures thereof.

Suitable cellulose ethers are, for example, carboxymethylcellulose (CMC), cetylcellulose (MC), ethylcellulose (EC), hydroxyethylcellulose (HEC), hydroxyethylmethylcellulose (HEMC) or hydroxypropylmethylcellulose (HPMC), hydroxyethyl-methyl- Cellulose, hydroxypropyl-methyl-cellulose, ethylhydroxyethyl-cellulose, carboxymethylhydroxyethyl-cellulose, or mixtures thereof.

Suitable carboxyvinyl polymers are, for example, polyacrylic acid, acrylate copolymers, or mixtures thereof.

Preferably, the gel (preferably lyogel) of the present invention contains the at least one gelling agent in an amount ranging from 0.1 wt% to 49.9 wt%, preferably 49.9 wt%, based on the total weight of the gel (preferably lyogel). ranges from 0.5 wt% to 45 wt%, more preferably from 1 wt% to 41 wt%, more preferably from 2 wt% to 37 wt%, more preferably from 3 wt% to 25 wt%, more preferably from 5 wt%. Contained in proportions ranging from 15 wt%.

Preferably, the gel (preferably lyogel) of the invention comprises:
(e) further comprising at least one pH adjusting substance, preferably an inorganic acid, an organic acid, an inorganic base, an organic base, or a mixture thereof.

Preferably, the pH value of said gel (preferably lyogel) at a temperature in the range from 2 to 50° C. and a pressure in the range from 800 to 1200 mbar is in the range from 4 to 11, preferably from 6 to 10.

Suitable inorganic acids are, for example, phosphoric acid, sulfuric acid, hydrochloric acid or mixtures thereof.

Suitable organic acids are, for example, acetic acid, sulfuric acid, toluenesulfonic acid, citric acid, barbituric acid, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, 4-(2-hydroxyethyl)-piperazine- ethanesulfonic acid, 4-(2-hydroxyethyl)-piperazine-1-propanesulfonic acid, 2-(N-morpholino)ethanesulfonic acid, or mixtures thereof.

Suitable inorganic bases are, for example, phosphates, hydrogen phosphates, dihydrogen phosphates, sulfates, hydrogen sulfates, ammonia, NaOH, KOH or mixtures thereof.

Suitable organic bases are, for example, tris(hydroxymethyl)-aminomethane, N-methylmorpholine, triethylamine, pyridine, or mixtures thereof.

Preferably, the gel (preferably lyogel) of the invention comprises:
(f) at least one soluble salt of a metal present in said at least one polar solvent (preferably water), said metal being a metal of main groups 1 to 3 of the Periodic Table of the Elements, preferably Soluble salts selected from the group consisting of alkali metals or alkaline earth metals and fluorides, chlorides, bromides, iodides, sulfates, hydrogen sulfates, phosphates, dihydrogen phosphates, hydrogen phosphates , tosylate, mesylate, formate, acetate, propionate, butanoate, oxalate, tartrate, fumarate, benzoate, citrate and/or mixtures thereof. , more preferably at least one anion selected from the group consisting of chloride, sulfate, hydrogen sulfate, formate, acetate, benzoate, citrate, and/or mixtures thereof. .

Preferably, the gel of the present invention (preferably a lyogel) contains the at least one soluble salt in the range of 0 wt% to 20 wt%, preferably 0.5 wt%, based on the total weight of the gel of the present invention (preferably a lyo gel). It is contained in a proportion ranging from 5 wt% to 15 wt%, more preferably from 0.7 wt% to 10 wt%, more preferably from 1 wt% to 7 wt%, and even more preferably from 1.5 wt% to 5 wt%.

Preferably, the gel (preferably lyogel) has a kinematic viscosity coefficient in the range of 1000 Pas to 5000 Pas.

The active or inactive invasion, attachment, and multiplication of a pathogen into a host is called infection. Infectious substances exist everywhere. For example, the human body is home to a large number of microorganisms that are typically kept in check by normal metabolism and a healthy immune system. However, for example, when the immune system is weakened, intense proliferation of pathogens and various pathological conditions caused by the pathogens may occur. Medicine has prepared specific drugs for many diseases caused by pathogens, such as antibiotics for bacteria, antifungals for fungi, or antivirals for viruses. However, the use of this silver bullet has been seen to increase the emergence of resistant pathogens, some of which are resistant to multiple drugs at the same time. Because of this development of resistant or multiresistant pathogens, the treatment of infectious diseases has become increasingly difficult. The clinical consequence of resistance is treatment failure, especially in immunosuppressed patients.

Unicellular or multicellular microorganisms can cause infections. The number of pathogens can be reduced and/or inactivated by administration of specific drugs, such as antibiotics, antifungals, or antivirals, that are specific to at least one pathogen. Administration of pathogen-specific drugs can be systemic and/or local.

In systemic administration, a specific drug directed against a pathogen is transferred to and distributed throughout the body through the blood and/or lymphatic systems of the body to be treated. When a specific drug that is specifically effective against pathogens is ingested systemically, side effects may occur due to degradation of the specific drug and/or, for example, biochemical conversion (metabolism) of the specific drug.

In topical administration of a specific agent against a pathogen, the agent is administered at the site where the agent is supposed to act therapeutically, for example, on the infected skin, without placing a significant burden on healthy skin. Thereby, systemic side effects can be largely avoided.

Superficial skin infections or soft tissue infections do not necessarily need to be treated with specific drugs that are specific to the pathogen, since specific drugs can be applied directly to the infected skin area.

The specific pathogen-specific drugs hitherto known in the art have rather severe side effects and interactions upon systemic and local administration. Moreover, even during topical administration, the development of resistance can occur due to unreliable patient compliance, especially in the case of antibiotic use.

An alternative here is photodynamic inactivation of microorganisms that are not known to be resistant to photodynamic inactivation. Regardless of the type of microorganism to be combated and the infection connected to it, the number of pathogens is reduced and/or the pathogens are killed. By way of example, mixtures of different microorganisms, such as fungi, bacteria, or different bacterial strains, can be suppressed.

The object of the invention is also achieved by providing a dispersion according to any one of claims 1 to 14 for use in photodynamic therapy for inactivating microorganisms. The microorganisms are preferably selected from the group consisting of viruses, archaea, bacteria, bacterial spores, fungi, fungal spores, protozoa, algae, and blood-borne parasites, and the dispersion is preferably Used in the treatment and/or prevention of tissue and/or gingival diseases.

The object of the present invention is also the photodynamic inactivation of microorganisms, including in particular viruses, archaea, bacteria, bacterial spores, fungi, fungal spores, unicellular animals, algae, blood-borne parasites, or combinations thereof. The method includes the following steps:
(A) contacting the microorganism with at least one dispersion according to any one of claims 1 to 14;
(B) irradiating the microorganism and at least one photosensitizer contained in the dispersion with electromagnetic radiation of appropriate frequency and energy density;

Preferably, the method of microbial inactivation of the invention is carried out in the photodynamic treatment of a patient and/or in the photodynamic sterilization of at least surfaces of objects and/or of at least surfaces of rooms.

In a preferred embodiment of the method of the present invention, the irradiation of the microorganism and the at least one photosensitizer is performed using electromagnetic radiation of suitable frequency and energy density. It is carried out in the presence of oxygen-containing gas.

Said at least one oxygen-donating compound and/or at least one oxygen-containing gas is preferably added before or during step (B) of the method of the invention.

in the form of at least one oxygen-containing compound and/or one at least one oxygen-containing gas before or during irradiation of the microorganism and the at least one photosensitizer with electromagnetic radiation of suitable frequency and energy density. Further addition of oxygen increases the yield of reactive oxygen species (ROS) produced, preferably oxygen groups and also singlet oxygen.

The object of the invention is also achieved by the use of at least one dispersion according to any one of claims 1 to 14 for the inactivation of microorganisms. The microorganisms preferably include viruses, archaea, bacteria, bacterial spores, fungi, fungal spores, protozoa, algae, blood-borne parasites, or combinations thereof.

The dispersions that can be used according to the invention have high yields of singlet oxygen after irradiation with electromagnetic radiation of appropriate wavelength and energy density.

In the method and/or use of the invention, the electromagnetic radiation is preferably in the visible spectral range, the ultraviolet and/or the infrared range. More preferably, the electromagnetic radiation has a frequency in the range 280-1000 nm, even more preferably 380-1000 nm.

More preferably, the electromagnetic radiation is 1 μW/cm ² to 1 kW/cm ² , even more preferably 1 mW/cm ² to 100 W/cm ² , even more preferably 2 mW/cm ² to 50 W/cm ² , even more preferably 6 mW/cm 2 It has an energy density of 7 mW/cm ² to 25 W/cm ² , more preferably 7 mW/cm ² to 25 W/cm ² .

The irradiation time can be varied depending on the type of microorganism and/or the severity of the infection. Preferably, the irradiation time is 1 μs to 1 h, more preferably 1 ms to 1000 s.

For example, the irradiation devices described in WO96/29943A1, EP0437 183 B1 or WO2013/172977A1 can be used for the irradiation.

Preferably, the irradiation device further comprises a device for the release of said at least one oxygen-containing compound, preferably a peroxide, and/or said at least one oxygen-containing gas, preferably oxygen.

Preferably, the electromagnetic radiation is generated with an artificial radiation source, for example a radiation source selected from the group of UV ultraviolet lamps, infrared lamps, fluorescent lamps, light emitting diodes, lasers or chemical lights.

Furthermore, the inventors have surprisingly found that at least one photosensitizer contained in the dispersion of the invention has a high affinity for microorganisms.

Based on the affinity, the at least one photosensitizer contained in the dispersion is capable of efficiently binding to microorganisms and locally sufficient singlet oxygen to inactivate, preferably kill, the microorganisms. cause

Furthermore, by providing at least one photosensitizer in the form of a dispersion of the present invention, the half-life of locally generated singlet oxygen can be reduced after irradiation with electromagnetic radiation of appropriate wavelength and energy density. , will be greatly extended.

After irradiating the dispersion of the invention with electromagnetic radiation having a suitable wavelength and energy density, the microorganisms are preferably inactivated by the generated reactive oxygen species (ROS), in particular oxygen groups and/or singlet oxygen. is killed.

Preferably, by increasing the half-life of locally generated singlet oxygen, the development of inactivation or decolonization of microorganisms is accelerated after irradiation with electromagnetic radiation of appropriate wavelength and energy density.

According to the invention, the term "decolonization" is understood as the removal, in particular the complete removal, of microorganisms.

Preferably, human and animal, especially mammalian body surfaces, such as the skin or mucous membranes, may be treated. In this preferred embodiment, at least one dispersion that can be used according to the invention is used for disinfection and/or decolonization of skin surfaces or soft body surfaces, preferably in connection with skin preservation.

In further preferred embodiments, the dispersions that can be used according to the invention are used for local and/or topical, nasal, oral, anal, vaginal or dermal administration.

Topical administration is understood as use on or inside the ear, in particular the external ear. External ear is also understood as administration outside the ear cartilage, pinna, ear lobe, ear canal, and tympanic membrane.

Local administration is also understood as administration on or inside the nose and/or in the paranasal sinuses, such as the maxillary, frontal and/or sphenoid sinuses.

Local administration is also understood as administration on the surface of the eye, in particular on the outer apical epithelial layer of the cornea, and/or on the external surface of the appendages of the eye, in particular the lacrimal organs, conjunctiva and/or eyelids.

Local administration is also understood as administration outside and distally of the epithelium of hollow organs, such as esophagus, gastrointestinal tract, gallbladder, bile ducts, larynx, trachea, fallopian tubes, uterus, vagina, ureters, bladder, urethra.

Local administration is also understood as administration on or inside the tooth, for example in root canals and/or gingival pockets and/or bone pockets.

In a further preferred embodiment, at least one dispersion which can be used according to the invention is preferably used for treating staphylococcal scalded skin syndrome, impetigo, skin abscesses, furuncle, carbuncles, cellulitis, cellulitis, acute lymphoma. infectious disease selected from the group consisting of adenopathy, pilonidal sinuses, pyoderma, purulent dermatitis, septic dermatitis, abscess dermatitis, erythrodermis, erysipelas, acne vulgaris, or fungal infection; , in particular for the production of pharmaceutical preparations for the prevention and/or treatment of viral, bacterial and/or fungal skin diseases.

In a further preferred embodiment, at least one dispersion that can be used according to the invention is used for the production of a preparation for wound healing, for example in healing problems after surgical therapeutic procedures.

Preferably, at least one dispersion that can be used according to the invention is used for disinfection and/or for reducing the number of pathogenic bacteria in infected wounds.

In a further preferred embodiment, at least one dispersion that can be used according to the invention is used to prevent infectious, in particular viral, bacterial infections in the ear, upper respiratory tract, oral cavity, pharynx, larynx, lower respiratory tract and/or esophagus. , and/or for the manufacture of pharmaceutical preparations for the prevention and/or treatment of fungal diseases.

The predominance of pathogenic microorganisms is, for example, the main cause of infections in the oral cavity. Therefore, a problem arises in that biofilms, which are composed of extremely complex microorganisms, are organized by interacting with each other. This biofilm, such as dental plaque or dental faeces, consists of multiple complex layers and contains proteins, carbohydrates, phosphates, and microorganisms. Dental plaque occurs especially where tooth surfaces cannot be kept free of deposits by natural or artificial cleaning. This situation makes it difficult to access the microorganisms contained in the biofilm.

Conventional treatments, such as antibiotics and mouthrinses or mechanical tooth cleaning, have been shown to have no direct effect on bacteria, e.g. in the case of antibiotics and mouthrinses. It is of limited use because of difficulties in dosing and administration, or because of adverse side effects that may not justify general use of the method.

For example, in the United States, there are 20 million root canals treated each year, of which approximately 2 million or more endodontic procedures are performed that could be avoided with improved root sterilization.

The method of the invention and the use of the invention are particularly suitable for the effective removal of microorganisms in the root canal system of human teeth, understood as root canals and dentinal tubules.

In a preferred embodiment, at least one dispersion that can be used according to the invention is used to treat infectious, in particular viral, bacterial and/or fungal diseases of the dental tissue, in particular plaque, caries, or pulpitis and/or infectious, in particular viral, bacterial and/or fungal diseases of the periodontium, in particular gingivitis, periodontitis, pulpitis or peri-implantitis. Used in the manufacture of preventive and/or therapeutic pharmaceutical preparations.

In a further preferred embodiment, at least one dispersion that can be used according to the invention is used for cleaning teeth, dentures and/or orthodontic bridges, or for nasal decolonization of microorganisms. .

For example, methicillin-resistant Staphylococcus aureus (MRSA) strains have a persistence of several months in nasal colonization and are highly environmentally resistant. Therefore, decolonization of the nose, eg, removal of microorganisms, usually reduces colonization in other body parts.

In a further preferred embodiment, at least one dispersion that can be used according to the invention is used in biological fluids, in particular medical blood products, in the inactivation of microorganisms.

Apparatus suitable for the irradiation of biological fluids are known to those skilled in the art and are described, for example, in WO 99/43790 A1, US 2009/0010806 A1 or WO 2010/141564 A2.

Suitable biological fluids include, for example, fresh frozen plasma, red blood cell concentrates, platelet concentrates, granulocyte concentrates, platelet-rich plasma, stem cell preparations, single blood clotting factor concentrates, human serum albumin, immunoglobulins, Contains blood and blood products, including fibrin glue, antithrombin, protein C, protein S, fibrinolytic agents, or combinations thereof.

In a preferred embodiment, at least one dispersion that can be used according to the invention is used for photodynamic disinfection of any surface. Photodynamic disinfection of surfaces causes photodynamic inactivation of microorganisms on the treated surface.

Suitable surfaces include, for example, synthetic resin, metal, glass, textile, wood, stone, or combinations thereof.

More preferably, the dispersion of the invention is used for photodynamic application of medical products, appliances, sanitary products, food packaging, beverages, furniture, building materials or rooms (e.g. floors, walls and/or windows). used for surface sterilization, surface cleaning, and/or surface coating.

More preferably, objects with thermally defined durability, for example objects made of thermoplastic synthetic resins, are treated or attacked with a disinfectant.

Objects with thermally limited durability can only be sterilized insufficiently, for example because they lose their shape or become brittle at slightly higher temperatures.

Moreover, inappropriate and/or excessive use of fungicides, for example due to active substance concentration and duration of action, and selection of hardy microorganisms, can lead to the development of resistance if the pathogen reduction effect is too low.

In a further preferred embodiment, the method of the invention is carried out, e.g. before implantation or after decolonization carried out to prevent resettlement of pathogenic microorganisms, e.g. periodontal pathogenic microorganisms. , used to prevent bacterial infections.

To prevent infection by microorganisms, the method of the invention can likewise be used to decolonize surfaces.

For example, contact between an immunosuppressed patient and a contaminated object usually results in an outbreak of an infectious disease, since immunosuppressed patients are usually susceptible to infection even when pathogen counts are low. In particular medical products, preferentially medical or dental instruments, more preferentially invasive dispersion medical instruments such as catheters, hollow probes, tubes or needles, before being introduced into the human body. must be sterilized.

Therefore, in a further preferred implementation, at least one dispersion according to the invention is used in medical products, in particular for example contact lenses, surgical instruments, dental drills, stomatoscopes, curettes, dental files, catheters, hollow Used to inactivate microorganisms on the surfaces of invasive medical devices such as probes, tubes, and needles.

Preferably, the medical product is selected from dressings, bandages, surgical instruments, catheters, hollow probes, tubes, or needles.

More preferably, medical products are understood as dental impression materials, impression trays, clips, splints or dentures (for example dental prostheses, crowns or implants) and, for example, hearing aids or contact lenses.

Preferably, the surface of any type of article is treated with at least one dispersion of the invention on the surface of a medical device and thereafter irradiated with electromagnetic radiation having a suitable frequency and energy density. This reduces and preferably prevents microbial colonization on the treated surfaces.

Preferably, the surface treatment is carried out by spraying, smearing, injecting, spraying, dipping or a combination thereof.

In this case, the irradiation is carried out immediately after the surface treatment with at least one dispersion that can be used according to the invention and/or at a later time before or after the use of the treated object, e.g. a medical product. I can.

In a further preferred embodiment, at least one dispersion that can be used according to the invention is used for the inactivation of microorganisms on the surface of food packaging.

Suitable food packaging includes, for example, containers made of glass, metal, plastic, paper, cardboard, or other combinations.

Suitable containers are, for example, treated with at least one dispersion that can be used according to the invention, before being filled with food or drink, and then treated with a suitable irradiation source producing electromagnetic radiation with a suitable frequency and energy density. It can be irradiated at A suitable food or drink is then packed into the sterilized container and the container is closed.

In a further preferred embodiment, at least one dispersion that can be used according to the invention is used for the inactivation of microorganisms on the surface of food products.

Suitable foods include, for example, meat, fish, eggs, seeds, sowing seeds, nuts, spices, fruits, or vegetables that can come into contact with Salmonella, Clostridium, E. coli or Campylobacter species. In particular, hatched eggs can be photodynamically sterilized as well.

Gastrointestinal infections refer to a group of diseases that are primarily manifested by symptoms in the upper gastrointestinal tract, such as vomiting, diarrhea, and stomach pain. Gastrointestinal infections are caused by viruses, bacteria, or parasites. Pathogens are often introduced by contaminated water and/or contaminated food.

Among the most known causes of gastrointestinal infections are, for example, Salmonella enterica, Campylobacter species, or E. coli, such as enterohemorrhagic E. coli (EHEC). Diarrhea with vomiting due to food poisoning is mainly caused by Staphylococcus.

In most cases, pathogens of gastrointestinal infections, such as Salmonella, enter the human gastrointestinal tract via food. The present inventors have realized that microorganisms on the surface of foods can be efficiently removed by the method of the present invention.

Salmonella, for example, is a bacterium that exists all over the world. Salmonella enterica is a typical food-borne disease that causes diarrhea. The pathogen thrives in the gastrointestinal tract of humans and animals. Salmonella can grow in unrefrigerated foods. This bacteria sometimes also enters food through improper kitchen hygiene, such as soiled cutting boards and/or knives.

Foods contaminated with Salmonella are often contaminated with raw or undercooked eggs and egg products, such as mayonnaise, egg-based creams or salads, or raw cake batter, to name a few. be. In many cases, the foods that are contaminated with Salmonella are likewise ice cream, raw meat, such as raw minced meat or tartare, raw meat sausage types, such as metwurst or salami. Salmonella can also persist on plant foods.

Campylobacter, for example, is a bacterium that is caused by infectious diarrhea and is present throughout the world. Campylobacter species primarily persist in the gastrointestinal tract of animals that do not cause disease themselves. In Germany, Campylobacter is the most common bacterial pathogen causing diarrhea.

The main source of Campylobacter infection is eating food contaminated with the bacteria. Transmission often occurs through poultry meat. Campylobacter cannot reproduce in food, but can survive for quite some time in the environment. Inadequate kitchen hygiene can also cause infections, for example, by cutting boards and/or knives that are not thoroughly cleaned after cooking raw meat.

In many cases, foods contaminated with Campylobacter include, for example, undercooked poultry and poultry products, raw milk or dairy products, undercooked ground meat or types of raw meat sausages, such as metwurst. , and contaminated drinking water, for example from well water installations.

Enterohemorrhagic Escherichia coli (EHEC) is found in the intestines of ruminants such as cows, sheep, goats, roe deer, or deer. This bacterium is excreted in the feces of infected animals. EHEC is relatively resistant and can survive in the environment for many weeks. It is highly contagious, and only a small amount of the pathogen is sufficient for transmission. The fur of cows and other ruminants may be contaminated with trace amounts of feces. Touching and petting animals can transfer germs to your hands and from your hands to your mouth. Playing on grasslands where ruminants are kept poses a risk of infection for children.

By using the method of the invention, surfaces of shoes, for example shoe soles, can likewise be sterilized in a simple manner.

Furthermore, the inventors have found that the method of the invention is suitable for animal products, such as fur, leather, wool, fibers or wool.

EHEC bacteria can adhere to and be further indirectly spread from touched objects, for example in the case of poor hand hygiene.

Transmission to humans occurs through food that is eaten raw or undercooked. Foods that are often contaminated with EHEC include, for example, raw milk and raw dairy products, raw or undercooked meat products, such as ground beef (e.g., hamburgers), and types of raw meat sausages that can be smeared. For example, tableurst. Similarly, foods that are often contaminated with EHEC include vegetables that have been contaminated with the pathogen through fertilization or contaminated water, unpasteurized juice made from contaminated fruit, and young seedlings. plant foods, such as seeds used in the cultivation of plants, and all foods to which food pathogens have been directly or indirectly transferred by contaminated hands or kitchen utensils.

Clostridium difficile, for example, is a bacterium that exists all over the world. In healthy humans, Clostridium difficile is a harmless intestinal bacterium. If the opposing species of the resident intestinal flora are suppressed by antibiotics, Clostridium difficile can proliferate and, in some cases, especially when substance-induced diarrhea has previously occurred, cause life-threatening diarrheal diseases, e.g. , produce toxins that can cause antibiotic-induced colitis.

Clostridium difficile is one of the most frequently present hospital bacteria (nosocomial pathogens). Additionally, Clostridium difficile can form persistent forms called spores that allow the bacterium to survive outside the gastrointestinal tract, sometimes for years. Transmission can therefore occur through objects and surfaces on which pathogens are deposited, such as toilets, door handles, handrails, and/or handrails.

Clostridium difficile is one of the most frequently present hospital bacteria (nosocomial pathogens). What's more, Clostridium difficile can form persistent forms called spores that allow the bacterium to survive outside the gastrointestinal tract, sometimes for years. Transmission can therefore occur through objects and surfaces on which pathogens are deposited, such as toilets, door handles, handrails, and/or handrails.

Clostridium difficile is one of the most frequently present hospital bacteria (nosocomial pathogens). What's more, Clostridium difficile can form persistent forms called spores that allow the bacterium to survive outside the gastrointestinal tract, sometimes for years. Transmission can therefore occur through objects and surfaces on which pathogens are deposited, such as toilets, door handles, handrails, and/or handrails.

The above-mentioned problems can be avoided through the use of the method of the invention, since after use of the method of the invention, the pathogen causing the disease is effectively removed on the contaminated surface.

In a further preferred embodiment, at least one dispersion that can be used according to the invention is used for the inactivation of microorganisms in a room, for example a dust-free room or an operating room. For example, after entering a room by atomization, atomization, injection, evaporation, the room can be irradiated with a suitable radiation source that produces electromagnetic radiation of suitable frequency and energy density, thereby , the microorganisms present are inactivated.

In a further preferred embodiment, at least one dispersion that can be used according to the invention is used for the inactivation of microorganisms in liquids or liquid preparations. Suitable liquids or liquid preparations are, for example, dispersion coatings, coolants, cutting oils, lubricants, brake fluids, lacquers, adhesives or oils. Preferably, the liquid formulation is a water-enriched formulation.

Preferably, the liquid is water.

Here, at least one dispersion that can be used according to the invention can be used for water purification for the food and beverage industry, the pharmaceutical industry, the chemical industry, the cosmetic industry, the electronic industry. Furthermore, at least one dispersion that can be used according to the invention can be used for the purification of drinking water and rainwater, for the treatment of sewage or for the purification of water for air conditioning technology.

Suitable objects are, for example, medical products, food packaging, sanitary products, textiles, handles, handrails, contact lenses, building materials, banknotes, coins, gaming chips, playing cards, sports equipment, textiles, tableware, tableware sets, etc. or electrical appliances.

Suitable objects are, for example, seals, membranes, sieves, filters, containers and/or hot water generators, hot water supply devices, air conditioners, humidifiers, cooling devices, refrigerators, drink vending machines, washing machines or dryers. It is a machine.

For example, small amounts of microorganisms can enter the air conditioner and exist there, at least for a short period of time, despite the filtration of externally supplied air. The metabolic products of this microorganism can cause a musty, stuffy odor.

Furthermore, for example, during operation of an air conditioner, moisture in the air is extracted and collected. Most of the condensate is removed and flows out, for example, through a condensate drain. Nevertheless, residual water remains on the evaporator surface of the air conditioner, especially when the temperature cannot be regulated because the air conditioner is not switched off unless the motor is switched off, for example in a passenger car.

Microorganisms, such as fungi and/or bacteria, which get onto the evaporator by the air, obtain an ideal moist and warm atmosphere on the spot and can spread unhindered.

By way of example, since mold is a health risk, air conditioning equipment must be regularly disinfected and any microorganisms present must be killed by use of the method of the invention.

When replacing filters of air conditioners, for example dust filters and/or pollen filters, in addition, the filter housing and the adjacent ventilation ducts can be cleaned by using the method of the invention. By cleaning the evaporator of the air conditioner, malodors generated by the air conditioner may also be removed.

Legionella, for example, is a bacterium that causes a variety of medical conditions in humans, such as influenza-like illnesses or pneumonia. Legionella bacteria particularly thrive at temperatures between 25°C and 45°C. Particularly in artificial water systems, such as building water pipes, this pathogen is provided with suitable growth conditions due to the temperatures present. Legionella bacteria can likewise grow in the sediments and/or coatings of pipeline systems. Thereby, the method of the invention can be used, for example, in combination with a method for removing deposits and/or coatings.

Legionella bacteria are transferred by atomized water. Droplets containing pathogens can spread in the air and be inhaled. Possible sources of infection are, for example, hot water supply equipment, in particular showers, humidifiers or taps, as well as cooling towers, air conditioners or other equipment that sprays water, such as sprayers, fog fountains. , decorative fountain, or similar. Infection is also possible in swimming pools due to waterfalls, slides, whirlpools, and/or fountains. Legionella infections can be prevented by using the method of the invention on contaminated object surfaces.

The method of the present invention can be applied, for example, to equipment or equipment equipped with water pipes and/or water containers, such as equipment or equipment used for fish farming.

Fish epidemics, for example, represent a major economic risk for all intensive fish farms where food fish are kept in small spaces. To combat fish diseases, for example, antibiotics and/or chemical additives are used. As chemical additives, for example, slaked lime (calcium hydroxide), hydrogen peroxide, peracetic acid preparations, copper sulfate, chloramines, sodium carbonate, sodium chloride or formaldehyde are used.

In order to reduce the use of antibiotics and/or the chemical additives mentioned above, at least one dispersion that can be used according to the invention can be added to fish farming equipment or equipment, such as aquaculture ponds, ponds, pumps, filters, pipes, nets. , fishing hooks, or foot mats. Similarly, for example, fish and/or litter can be photodynamically sterilized. Additionally, terrestrial vivariums, aquarium containers, sand, gravel, and/or green plants can be photodynamically sterilized before and/or during use.

Suitable appliances include, for example, cooker hot plates, headphones, hands-free microphones, headsets, mobile phones, and operating elements such as buttons, switches, touch screens, or keyboards. Suitable building materials include, for example, concrete, glass, sand, gravel, wall coverings, plaster, finishing mortar, or the like.

Suitable finishing wall materials are, for example, mirror boards, tiles, solid wood boards, medium density fibreboards, plywood, polyplywood, fiber-reinforced concrete boards, gypsum board boards, gypsum fibreboards, and synthetic resins, styrofoam, and/or or wallpaper consisting of cellulose.

For example, at least one dispersion that can be used according to the invention can be used for mold removal.

Preferably, the mold-infested surface is treated with at least one dispersion usable according to the invention and then irradiated with an irradiation source producing electromagnetic radiation of suitable frequency and energy density; This then reduces, preferably inactivates, the mold present on the treated surface.

In the above-described preferred embodiments of the use of the invention or the method of the invention, the irradiation of the microorganism and the at least one dispersion that can be used according to the invention comprises at least one irradiation using electromagnetic radiation of suitable frequency and energy density. at least one oxygen-containing gas, preferably oxygen.

Said at least one oxygen-providing compound and/or at least one oxygen-containing gas may be added before or during irradiation, preferably using electromagnetic radiation of appropriate frequency and energy density.

in the form of at least one oxygen-containing compound and/or one at least one oxygen-containing gas before or during irradiation of the microorganism and the at least one photosensitizer with electromagnetic radiation of suitable frequency and energy density. Further addition of oxygen increases the yield of reactive oxygen species (ROS) produced, preferably oxygen groups and also singlet oxygen.

According to aspect 1, the present invention relates to a photosensitizer dispersion, the photosensitizer dispersion comprising:
(a) at least one photosensitizer;
(b) at least one surfactant; and (c) at least one surfactant.

According to aspect 2, the present invention relates to a photosensitizer dispersion according to aspect 1, wherein said at least one photosensitizer is positively charged, negatively charged or uncharged. and the at least one photosensitizer has a) at least one uncharged protonatable nitrogen atom and/or b) at least one positively charged nitrogen atom. More preferably, it contains at least one organic group.

According to aspect 3, the present invention relates to a photosensitizer dispersion according to any one of aspects 1 to 2, wherein the at least one photosensitizer is phenalenone, curcumin, flavin, porphyrin, porphycene, xanthine. Pigments, coumarins, phthalocyanines, phenothiazine compounds, anthracene dyes, pyrenes, fullerenes, perylenes, and mixtures thereof, preferably phenalenone, curcumin, flavin, porphyrin, phthalocyanine, phenothiazine compounds, and mixtures thereof, more preferably phenalenone, curcumin, selected from the group consisting of flavins, and mixtures thereof.

According to aspect 4, the invention relates to a photosensitizer dispersion according to any one of aspects 1 to 3, wherein said at least one photosensitizer has the formula (2) to (28), and mixtures thereof.

According to aspect 5, the present invention relates to a photosensitizer dispersion according to any one of aspects 1 to 4, wherein the at least one photosensitizer has formulas (32) to (49), (51 ) to (64), and mixtures thereof.

According to aspect 6, the present invention relates to a photosensitizer dispersion according to any one of aspects 1 to 5, wherein the at least one photosensitizer has formulas (75) to (104b), (105 ), and mixtures thereof.

According to aspect 7, the present invention relates to a photosensitizer dispersion according to any one of aspects 1 to 6, wherein the at least one photosensitizer has formulas (2) to (28), (32 ) to (49), (51) to (64), (75) to (104b), (105), and mixtures thereof.

According to aspect 8, the present invention relates to the photosensitizer dispersion according to any one of aspects 1 to 7, in which an anion is selected as a counter ion to the positively charged nitrogen atom, and the anion fluoride, chloride, bromide, iodide, sulfate, hydrogen sulfate, phosphate, dihydrogen phosphate, hydrogen phosphate, tosylate, mesylate, formate, acetate, propionate, butanoate, oxalate, tartrate, fumarate, benzoate, citrate, and selected from the group consisting of mixtures. selected from the group consisting of.

According to aspect 9, the invention relates to a photosensitizer dispersion according to any one of aspects 1 to 8, wherein said dispersion has a concentration of 0.1 μM to 1000 μM, preferably 1 μM to 750 μM, more preferably 2 μM at least one photosensitizer as described above at a concentration in the range of ˜500 μM.

According to aspect 10, the invention relates to a photosensitizer dispersion according to any one of aspects 1 to 9, wherein said at least one surfactant comprises at least one polar solvent, preferably water. There is.

According to aspect 11, the invention relates to a photosensitizer dispersion according to any one of aspects 1 to 10, wherein said dispersion contains at least 0.1 wt%, preferably at least 0.5 wt%, more preferably at least 1 wt%, more preferably at least 4 wt%, more preferably at least 10 wt%, more preferably at least 35 wt%, more preferably at least 50 wt%, more preferably contains at least one polar solvent, preferably water, in a proportion of at least 51% by weight.

According to aspect 12, the invention relates to a photosensitizer dispersion according to any one of aspects 1 to 11, wherein said dispersion has a .1 wt% to 99.8 wt%, preferably 0.5 wt% to 99 wt%, more preferably 4 wt% to 98 wt%, more preferably 10 wt% to 97 wt%, more preferably 35 wt%. In the range of ~96 wt%, more preferably in the range of 50 wt% to 95 wt%, more preferably in the range of 51 wt% to 94 wt%, more preferably in the range of 53 wt% to 93 wt%, more preferably in the range of 70 wt% to 92 wt%. in proportion to said at least one polar solvent, preferably water.

According to aspect 13, the present invention relates to a photosensitizer dispersion according to any one of aspects 1 to 12, wherein the at least one surfactant is an anionic surfactant as described above, a cationic surfactant as described above. Surfactants, selected from the group consisting of amphoteric surfactants as described above and mixtures thereof, preferably nonionic surfactants as described above, anionic surfactants as described above and mixtures thereof.

According to aspect 14, the present invention relates to a photosensitizer dispersion according to any one of aspects 1 to 13, wherein said dispersion has a .1 wt% to 65 wt%, preferably 1 wt% to 55 wt%, more preferably 3 wt% to 50 wt%, more preferably 5 wt% to 41 wt%, more preferably 7 wt% to 37 wt%. The at least one surfactant is present in a proportion ranging from 9 wt% to 30 wt%, more preferably from 10 wt% to 27 wt%.

According to aspect 15, the present invention relates to a photosensitizer dispersion according to any one of aspects 1 to 14, in which the nonionic surfactant is a polyalkylene glycol ether as described above, an alkyl glucoside as described above, selected from the group consisting of alkyl polyglycosides as described above, alkyl glycoside esters as described above and mixtures thereof.

According to aspect 16, the present invention relates to a photosensitizer dispersion according to any one of aspects 1 to 15, wherein the anionic surfactant is an alkyl carboxylate as described above, an alkyl sulfonate as described above, or as an alkyl sulfonate as described above. selected from the group consisting of alkyl sulfates, alkyl phosphates as described above, alkyl polyglycol ether sulfates, sulfonates of alkyl carboxylic acids as described above, N-alkyl sarcosinates as described above, and mixtures thereof.

According to aspect 17, the present invention relates to a photosensitizer dispersion according to any one of aspects 1 to 16, wherein the cationic surfactant is a quaternary alkyl ammonium salt as described above, an ester quat as described above. , the above-mentioned acylated polyamines, the above-mentioned benzyl ammonium salts or mixtures thereof.

According to aspect 18, the invention relates to a photosensitizer dispersion according to any one of aspects 1 to 17, wherein said dispersion comprises an acyclic compound as defined above having from 5 to 30 carbon atoms. Alkanes, cyclic alkanes as defined above having from 5 to 13 carbon atoms, perfluoroalkane as defined above having from 5 to 20 carbon atoms, preferably having from 4 to 20 carbon atoms, as defined above At least one liquid comprising at least one non-polar solvent selected from the group consisting of monocarboxylic esters, polycarboxylic esters as described above, preferably having from 6 to 20 carbon atoms, and mixtures thereof. It further includes a non-polar phase.

According to aspect 19, the invention relates to a photosensitizer dispersion according to any one of aspects 1 to 18, wherein said dispersion contains at least 0.1 wt%, preferably at least 0.5 wt%, more preferably at least 1 wt%, more preferably at least 4 wt%, more preferably at least 10 wt%, more preferably at least 35 wt%, more preferably It comprises at least one non-polar solvent in a proportion of at least 50 wt%, more preferably at least 51 wt%.

According to aspect 20, the invention relates to a photosensitizer dispersion according to any one of aspects 1 to 19, wherein said dispersion has a .1 wt% to 99.8 wt%, preferably 0.5 wt% to 99 wt%, more preferably 1 wt% to 96 wt%, more preferably 1.5 wt% to 90 wt%. , more preferably in the range of 3 wt% to 80 wt%, more preferably in the range of 5 wt% to 75 wt%, more preferably in the range of 10 wt% to 60 wt%, more preferably in the range of 12 wt% to 49 wt%. , comprising at least one non-polar solvent as described above.

According to aspect 21, the present invention relates to a photosensitizer dispersion according to any one of aspects 1 to 20, wherein said dispersion has from 2 to 12 carbon atoms and from 1 to 6 carbon atoms. It contains at least one alkanol, preferably having OH groups.

According to aspect 22, the invention relates to a photosensitizer dispersion according to any one of aspects 1 to 21, wherein said dispersion contains 0 wt. % to 50 wt%, preferably in the range 0.1 wt% to 40 wt%, more preferably in the range 0.5 wt% to 35 wt%, more preferably in the range 1 wt% to 30 wt%. The above in a proportion in the range of 1.5 wt% to 25 wt%, more preferably in the range of 5 wt% to 20 wt%, more preferably in the range of 7 wt% to 19 wt%, more preferably in the range of 10 wt% to 17 wt%. Contains at least one alkanol.

According to aspect 23, the invention relates to a photosensitizer dispersion according to any one of aspects 1 to 22, wherein said dispersion at a pressure in the range from 800 to 1200 mbar and a temperature in the range from 2 to 50°C. is a microemulsion, preferably an oil-in-water (O/W) microemulsion, a water-in-oil (W/O) microemulsion or a bicontinuous microemulsion, preferably an oil-in-water (O/W) microemulsion or an oil-in-oil microemulsion. A water-type (W/O) microemulsion.

According to aspect 24, the invention relates to a photosensitizer dispersion according to any one of aspects 1 to 23, wherein said dispersion is a microemulsion, preferably an oil-in-water (O/W) microemulsion, contains or is
(a) the above phenalenone, the above curcumin, the above flavin, the above porphyrin, the above porphycene, the above xanthine pigment, the above coumarin, the above phthalocyanine, the above phenothiazine compound, the above anthracene dye, the above pyrene, The above fullerenes, the above perylenes, and mixtures thereof, more preferably the above phenalenones, the above curcumins, the above flavins, the above porphyrins, the above phthalocyanines, the above phenothiazine compounds, and mixtures thereof, more preferably the above phenalenone, the above-mentioned curcumin, the above-mentioned flavin, and mixtures thereof, more preferably formulas (2) to (25), (32) to (49), (51) to (64), (75) to (105) ) and mixtures thereof;
(b) at least one polar solvent, preferably water;
(c) nonionic surfactants as described above, anionic surfactants as described above, cationic surfactants as described above, amphoteric surfactants as described above and mixtures thereof, preferably nonionic surfactants as described above; at least one surfactant selected from the group consisting of anionic surfactants as described above and mixtures thereof, and (d) an acyclic alkane as described above having from 5 to 30 carbon atoms, from 3 to 13 cyclic alkanes as described above having carbon atoms, perfluoroalkanes as described above having from 5 to 20 carbon atoms, monocarboxylic acid esters as described above having from 4 to 20 carbon atoms, at least one non-polar solvent selected more preferably from the abovementioned polycarboxylic esters having 20 carbon atoms and mixtures thereof, and (e) optionally having 1 to 6 OH groups. It preferably contains at least one alkanol selected from the group consisting of the abovementioned alkanols and mixtures thereof, having from 2 to 12 carbon atoms.

According to aspect 25, the invention relates to a photosensitizer dispersion according to any one of aspects 1 to 24, wherein said dispersion is an oil-in-water (O/W) microemulsion (preferably any more preferably in the range of 0.1 wt% to 49.9 wt%, preferably in the range of 0.5 wt to 48 wt%, more preferably in the range of 1 wt to 45 wt%, also based on the total weight of the microemulsion. at least one non-polar solvent in a proportion ranging from 3 wt.% to 40 wt.%, more preferably from 5 wt. In the range of 50 wt to 99.8 wt%, preferably in the range of 51 wt to 99 wt%, more preferably in the range of 52 wt to 96 wt%, more preferably in the range of 53 wt to 90 wt%, based on the total weight of the microemulsion. , more preferably at least one surfactant, preferably water, in a proportion ranging from 54 wt to 85 wt %, and preferably from 0.1 wt to 45 wt %, in each case based on the total weight of the microemulsion. preferably in the range of 0.5 wt to 40 wt%, more preferably in the range of 1 wt to 35 wt%, more preferably in the range of 3 wt to 30 wt%, more preferably in the range of 5 wt to 27 wt%. at least one surfactant, preferably in a proportion ranging from 7 wt.% to 25 wt.%, more preferably from 10 wt.% to 20 wt.%, and optionally further, in each case based on the total weight of the microemulsion; In the range of 0 wt to 50 wt%, preferably in the range of 0.1 wt to 40 wt%, more preferably in the range of 0.5 wt to 35 wt%, more preferably in the range of 1 wt to 30 wt%, more preferably 1.5 wt. at least one alkanol) in a proportion ranging from ~25wt%, more preferably from 5wt to 20wt%, more preferably from 7wt to 19wt%, more preferably from 10wt to 17wt%. .

According to aspect 26, the invention relates to a photosensitizer dispersion according to any one of aspects 1 to 25, wherein said dispersion preferably contains an inorganic acid, an organic acid, an inorganic base, an organic base, It further includes at least one pH adjusting substance which is a salt or a mixture thereof.

According to aspect 27, the present invention relates to a photosensitizer dispersion according to any one of aspects 1 to 26, wherein the dispersion comprises the above-mentioned carboxymethyl polymer, the above-mentioned polyacrylamide, the above-mentioned alginate, It further comprises at least one gelling agent selected from the group consisting of the above-mentioned cellulose ethers and mixtures thereof.

According to aspect 28, the invention relates to a photosensitizer dispersion according to any one of aspects 1 to 27, wherein said dispersion at a pressure in the range from 800 to 1200 mbar and a temperature in the range from 2 to 50°C. comprises or is a gel, preferably a dispersion gel.

According to aspect 29, the present invention provides a method for controlling the photodynamic activity of microorganisms preferably selected from the group consisting of viruses, archaea, bacteria, bacterial spores, fungi, fungal spores, protozoa, algae, and blood-borne parasites. The present invention relates to the use of a photosensitizer dispersion according to any one of embodiments 1 to 28 for inactivation.

According to aspect 30, the invention relates to the use according to aspect 29 for surface cleaning and/or surface coating of objects.

According to aspect 31, the invention provides a method according to any one of aspects 29 to 30 for surface cleaning and/or surface coating of medical products, food packaging, textile products, building materials, electronic devices, furniture or sanitary products. regarding such use.

According to aspect 32, the invention relates to the use according to any one of aspects 29 to 31 for the sterilization of liquids.

According to aspect 33, the invention relates to the use according to any one of aspects 29 to 32 for the sterilization of food products.

According to aspect 34, the present invention provides for the photodynamic analysis of microorganisms preferably comprising viruses, archaea, bacteria, bacterial spores, fungi, fungal spores, protozoa, algae, blood-borne parasites or combinations thereof. Regarding the method for inactivation, the method comprises the following steps:
(A) contacting the microorganism with at least one dispersion according to any one of aspects 1-28; and (B) applying electromagnetic radiation of a suitable frequency and energy density to the microorganism and the dispersion. irradiating at least one photosensitizer contained in the article.

The invention is illustrated below through figures and examples, but is not limited thereto.
FIG. 1 shows the average values of the contact angles of the microemulsions E1 to E4 without photosensitizer and of the aqueous ethanol solution, measured according to the concentrations indicated in Example 1. Figure 2 shows the measured contact angles of a microemulsion diluted with water (DMS; TWEEN® 20/1,2-pentanediol (1:3); water) measured in Example 1. The average value is shown. FIG. 3 shows the time-resolved singlet oxygen spectra measured in Example 1 for the photosensitizer TMPyP in water (w), microemulsion E1 (E1) or microemulsion E2 (E2). Figure 4 shows the time-resolved singlet oxygen spectra measured in Example 1 for photosensitizer SA-PN-01a in water (w), microemulsion E1 (E1) or microemulsion E2 (E2). There is. Figure 5 shows the time-resolved singlet oxygen spectra measured in Example 1 for photosensitizer FL-AS-1a in water (w), microemulsion E1 (E1) or microemulsion E2 (E2). There is. Figure 6a shows the results of the phototoxicity test determined in Example 1 for the photosensitizer SA-PN-01a in water at the indicated concentrations. Figure 6b shows the results of the phototoxicity test determined in Example 1 for the microemulsion E2 (E2) photosensitizer SA-PN-01a at the indicated concentrations. FIG. 7 shows the average values of the contact angles measured in Example 3 for gels G2 and G3 without photosensitizer, to which corresponding amounts of the indicated surfactants were added. FIG. 8 shows the time-resolved singlet oxygen spectrum measured in Example 3 for the photosensitizer TMPyP in gel G3. FIG. 9 shows the wavelength-resolved singlet oxygen spectrum measured in Example 3 for the photosensitizer TMPyP in gel G3.

All chemicals used were purchased from common vendors (TCI, ABCR, Acros, Merck, and Fluka) and used without further purification. Solvents were distilled and, if necessary, dried using conventional methods before use. Dry DMF was purchased from Fluka (Taufkirchen, Germany). Thin layer chromatography was carried out on thin layer aluminum foil coated with silica gel 60 F254 from Merck (Darmstadt, Germany). Preliminary chromatography was performed on commercially available glass plates coated with silica gel 60 (20 cm x 20 cm, Carl Roth GmbH& Co. KG, Karlsruhe, Germany). Compounds were detected with UV light (λ=254 nm, 333 nm) and partially visually or stained with ninhydrin. Chromatography was performed on silica gel (0.060-0.200) from Acros (Waltham, USA). NMR spectra were measured on a Bruker spectrometer Avance 300 (300 MHz [1H-NMR], 75 MHz [13C-NMR]) (Bruker Corporation, Billerica, USA). All compounds are listed in δ [ppm] relative to an external standard (tetramethylsilane, TMS). Each coupling constant is given in Hz; signal typology: s = singlet, d = doublet, t = triplet, m = multiplet, dd = double doublet, br = broad . The integral determines the relative number of atoms. The signal in the carbon spectrum is uniquely determined by the DEPT method (pulse angle: 135°). Error limits: 0.01 ppm for 1H-NMR, 0.1 ppm for 13C-NMR, and 0.1 Hz for coupling constants. The respective solvent used is listed for each spectrum. IR spectra were recorded on a Biorad spectrometer Excalibur FTS 3000 (Bio-Rad Laboratories GmbH, Munich, Germany). ES-MS was measured on a ThermoQuest Finnigan TSQ 7000 spectrometer, all HR-MS was detected on a ThermoQuest Finnigan MAT 95 (each from Thermo Fisher Scientific Inc, Waltham, USA), and argon was detected using FAB-ionization (Fast Atom Bombardement). It was used as an ionizing gas for Melting points were determined using a melting point measuring device Buchi SMP-20 (Buchi Labortechnik GmbH, Essen, Germany) using glass capillary tubes. All UV/Vis spectra were recorded on a Varian Cary 50 Bio UV/VIS spectrometer and fluorescence spectra on a Varian Cary Eclipse spectrometer. Absorption and emission measurement solvents of special spectrometer purity were purchased from Acros or Baker, or Uvasol was purchased from Merck. Millipore water (18 MΩ, Milli QPlus) was used in each measurement.

In the examples below, the following photosensitizers were used:

1. ) 5,10,15,20-tetrakis(1-methyl-4-pyridyl)-porphyrin-tetra-(p-toluenesulfonic acid)
(TMPyP, M=1363.65g/mol)

TMPyP was purchased commercially from TCI Germany GmbH (Eschborn, Germany).

2. ) 2-(4-pyridinyl)methyl)-1H-phenalen-1-one-chloride
(SA-PN-01a, M = 307.78g/mol),

Chloride of the compound having chemical formula (24)

SA-PN-01a was made according to EP 2 678 035 A2, Example 7, which describes the synthesis. The ¹ H-NMR spectrum in DMSO-d6 was the same as that disclosed in the literature.

3a. ) 10-[2-({[(tert-butyl)oxy]carbonyl}amino)eth-1-yl]-7,8-dimethyl-[3H,10H]-benzo[g]pteridine-2,4-dione (flavin 32a)

Synthesis other than commercially available precursors was performed according to the procedure published in Butenandt, J. et al. (2002). The ¹ H-NMR spectrum in DMSO-d6 was identical to the spectrum disclosed in the literature.

3b. ) 10-(2-aminoeth-1-yl)-7,8-dimethyl-[3H,10H]-benzo[g]pteridine-2,4-dione-hydrochloride (FL-AS-H-1a; M =321.77g/mol),

Chloride of the compound having the chemical formula (32)

Flavin 32a (2.0 mmol) was dissolved in dichloromethane (100 ml), HCl-diethyl ether (10 ml) was added dropwise and the reaction mixture was stirred overnight in a dehumidified dark place. The precipitate was sucked up, washed with diethyl ether, and then dried. The 1H-NMR spectrum in DMSO-d6 was identical to the spectrum disclosed in the literature.

4a) 3,10-bis[2'-(tert-butyloxycarbonylamino)-1'-ethyl]-7,8-dimethylbenzo[g]-pteridine-2,4-dione (flavin 64a)

The synthesis of flavin 64a other than flavin 32a was performed according to the procedure published in Svoboda J. et al. (2008). The 1H-NMR spectrum in DMSO-d6 was identical to the spectrum disclosed in the literature.

4b) 3,10-bis(2'-amino-1'-ethyl)-7,8-dimethylbenzo[g]pteridine-2,4-dione-dihydrochloride (FL-AS-H-2; M= 401.29g/mol),

Dichloride of compound (64)

Flavin 64a (2.0 mmol) was dissolved in dichloromethane (100 ml), HCl-diethyl ether (10 ml) was added dropwise and the reaction mixture was stirred overnight in a dehumidified dark place. The precipitate was sucked up, washed with diethyl ether, and then dried. The ¹ H-NMR spectrum in DMSO-d6 was identical to the spectrum disclosed in the literature.

5. Synthesis of compounds having chemical formulas (26), (27), (28a), and (28):

スキーム１：化学式（２６）および（２７）を有する化合物の合成；
条件５ａ）ＭｅＯＨ、メチルアミン、ＲＴ、一晩、５０℃、２～１０時間、６０～７５％；
５ｂ）トリメチルアミン、エタノール、ＲＴ、一晩、５０℃、５時間、８３％；

Scheme 1: Synthesis of compounds having chemical formulas (26) and (27);
Conditions 5a) MeOH, methylamine, RT, overnight, 50°C, 2-10 hours, 60-75%;
5b) Trimethylamine, ethanol, RT, overnight, 50°C, 5 hours, 83%;

スキーム２：化学式（２８）および（２８ａ）を有する化合物の合成；
条件５ｃ）Ｎ，Ｎ’－ジ－Ｂｏｃ－Ｎ’’－トリフリルグアニジン、ＤＣＭ、ＮＥｔ_３、０℃、その後ＲＴ、４時間、８８％；
５ｄ）Ｅｔ_２Ｏ中のＨＣｌ、ＤＣＭ、ＲＴ、６時間、５０℃、５時間、９６％。

Scheme 2: Synthesis of compounds having chemical formulas (28) and (28a);
Condition 5c) N,N′-di-Boc-N″-trifurylguanidine, DCM, NEt ₃ , 0° C. then RT, 4 h, 88%;
5d) HCl in _Et2O , DCM, RT, 6 h, 50<0>C, 5 h, 96%.

5a) N-methyl-N-(1-oxo-1H-phenalen-2-yl)methanaminium-chloride
Chloride of the compound having formula (27) An ice-cold solution of methylamine in methanol (40 mL, 10%) was dissolved in 2-chloromethyl-1H-phenalen-1-one (1) (113 mg, 0.5 mmol) in dropwise form for over 1 hour. After stirring for 30 hours at room temperature, excess amine and solvent were removed in a stream of nitrogen. The residue was dissolved in dichloromethane (DCM)/ethanol (4:1) and precipitated by adding diethyl ether. The product was centrifuged (60 min, 4400 rpm, 0°C) and the supernatant was discarded. This process was repeated one more time. The residue was then suspended in diethyl ether. After a yellow solid precipitated, the supernatant was decanted and discarded. This process was repeated twice. The product (101 mg, 0.39 mmol) was a tan powder.
¹ H-NMR (300MHz, CDCl ₃ ): δ[ppm]=8.66(d,J=7.4Hz,1H),8.28~8.20(m,2H),8.08(d,J=8.3Hz,1H),7.94 (d,J=7.0Hz,1H),7.80(t,J=7.7Hz,1H)7.67~7.59(m,1H),4.20(s,2H),2.79(s,3H),
MS(ESI-MS, _CH2Cl2 /MeOH+ _10mmolNH4OAc ):e _/ z(%)=224.1(MH ⁺ ,100%),
Molecular weight (MW)=224.28+35.45g/mol, molecular formula (MF)=C ₁₅ H ₁₄ NOCl.

5b) N,N,N-trimethyl-1-(1-oxo-1H-phenalen-2-yl)methanaminium-chloride
(SA-PN-02a)
Chloride 2-(chloromethyl)-1H-phenalen-1-one (1) (230 mg, 1 mmol) of a compound having chemical formula (26) - ethanol (60 mL) was poured into a Schlenk flask. Triethylamine (5 mL, 5.6 M, 23 mmol) in ethanol was added through the wall via syringe. The solution was stirred in the dark overnight. Stirring was then continued for 30 minutes at 50°C. The volume of solvent was concentrated to 3 mL. Diethyl ether (50 mL) was added to completely precipitate the product. The product was centrifuged (60 min, 4400 rpm, 0°C) and the supernatant was discarded. The residue was suspended in diethyl ether. After a yellow solid precipitated, the supernatant was decanted and discarded. This process was repeated twice. The solid was dried under reduced pressure to give a yellow powder (210 mg, 0.73 mmol).
¹ H-NMR (600MHz, D ₂ O): δ[ppm]=8.02(d,J=8Hz,1H),7.97(d,J=6.3Hz,1H),7.92(d,J=8.2Hz,1H ),7.77(s,1H),7.62(d,J=7Hz,1H),7.50(t,J=7.8Hz,1H),7.45(t,J=7.8Hz,1H),4.12(s,2H) ,2.98(s,9H),
MS(ESI-MS, _CH2Cl2 /MeOH+ _10mmolNH4OAc ):e _/ z(%)=252.1(100,M ⁺ ),
MW=287.79g/mol,
MF= _C17H18NOCl ;

5c) 1-((1-oxo-1H-phenalen-2-yl)methyl)-1-methyl-2,3-di(tert-butoxycarbonyl)guanidine
Compound having chemical formula (28a)
N,N'-di-Boc-N''-triflylguanidine (0.41 g, 1.05 mmol) in dichloromethane (10 mL) was poured into a dry 25 mL round bottom flask. Triethylamine (0.3 g, mL, 0.39 mL, 3 mmol) was added slowly at 2-5° C. under dehumidified conditions. Compound 3 (130 mg, 0.5 mmol) was added in one portion. After stirring at room temperature for 5 hours, it was diluted with dichloromethane (30 mL) and the solution was transferred to a separatory funnel. The organic phase was washed with aqueous potassium hydrogen sulfate solution, saturated sodium bicarbonate solution (10 mL) and saturated brine, dried over MgSO ₄ and filtered. It was then concentrated by rotary evaporation. The crude product was purified by column chromatography using acetone/petroleum ether (1:2) to give the product as a yellow solid (0.21 g). For further purification, the material was dissolved in acetone (1 mL) and precipitated with petroleum ether (14 mL). The precipitate was sucked up and washed with petroleum ether.
¹ H-NMR (300MHz, CDCl ₃ ): δ[ppm]=8.63(d,J=7.3Hz,1H),8.21(d,J=7.9Hz,1H),8.03(d,J=8.2Hz,1H ),7.85~7.70(m,3H),7.67~7.54(m,1H),4.59(s,2H),3.01(s,3H),1.50(s,9H),1.48(s,9H),
MS(ESI-MS, _CH2Cl2 /MeOH+ _10mmolNH4OAc ):e/z ₍ %)=466.1(MH ⁺ ,100%),
MW=465.53g/mol,
_{MF = C26H31N3O5 _}

5d) 1-((1-oxo-1H-phenalen-2-yl)methyl)-1-methyl-guanidinium-chloride
(SA-PN-24d)
Chloride of Compound Having Formula (28) Preparation and purification of the compound was carried out under conditions protecting from light. Compound 5 (200 mg, 0.45 mmol) was added to dichloromethane (20 mL, dried over CaCl _CaCl2 ). A saturated solution of HCl in diethyl ether (2 mL) was added dropwise. After stirring for 4 hours at room temperature under dehumidified conditions, the solution was divided into two Blue Caps and diethyl ether was poured into 15 mL. The product was centrifuged (60 min, 4400 rpm, 0°C) and the supernatant was discarded. The residue was suspended in diethyl ether. After a yellow solid precipitated, the supernatant was decanted and discarded. This process was repeated twice. Following this, the product was dried under reduced pressure to obtain 130 mg of a yellow powder.
¹ H-NMR (300MHz, DMSO-d6): δ[ppm]=8.60~8.47(m,4H),8.33~8.24(m,2H),8.16~8.09(m,2H),7.98~7.89(m, 2H),7.84~7.73(m,4H),7.57~7.48(m,7H),4.55~4.42(m,4H),3.05(s,6H),
MS(ESI-MS, _CH2Cl2 /MeOH+ _10mmolNH4OAc ):e/z(%)=266.1(MH ⁺ ,100%) _;
MW=266.3+35.45=301.75g/mol;
MF=C ₁₆ H ₁₆ N ₃ OCl

Example 1:
A) Preparation of different water-containing microemulsions The wt% of the components of microemulsions E1 to E4 shown below are each based on the total weight of the respective microemulsion without photosensitizer.

Microemulsion E1: Microemulsion consisting of DMS, SDS and 1-pentanol, and water. Here, the mass ratio of SDS to 1-pentanol is constant at 1:2.
20.0wt% dimethylsuccinic acid (DMS)
8.33wt% sodium dodecyl sulfate (SDS)
16.67wt% 1-pentanol 55.0wt% water

Microemulsion E2: Microemulsion consisting of DMS, SDS and 1,2-pentanediol, and water. Here, the mass ratio of SDS to 1,2-pentanediol is constant at 1:2.
20.0wt% dimethylsuccinic acid (DMS)
8.33wt% sodium dodecyl sulfate (SDS)
16.67wt% 1,2-pentanediol 55.0wt% water

Microemulsion E3: Microemulsion consisting of DMS, TWEEN® 20 and 1,2-pentanediol, and water. Here, the mass ratio of TWEEN® 20 to 1,2-pentanediol is constant at 1:3.
10.0wt% dimethylsuccinic acid (DMS)
3.75wt% TWEEN (registered trademark) 20
11.25wt% 1,2-pentanediol 75.0wt% water

Microemulsion E4: Microemulsion consisting of DMS, TWEEN® 20 and 1,2-propanediol, and water. Here, the mass ratio of TWEEN® 20 to 1,2-propanediol is constant at 1:3.
10.0wt% dimethylsuccinic acid (DMS)
3.75wt% TWEEN (registered trademark) 20
11.25wt% 1,2-propanediol 75.0wt% water

The corresponding microemulsions E1 to E4 are first prepared without photosensitizer. Now all ingredients except water were weighed and mixed in order. After a homogeneous mixture was obtained, a suitable amount of water was added with continued stirring.

For example, the production of 100 g of microemulsion E4 was carried out by weighing 3.75 G of TWEEN® 20, 11.25 g of 1,2-propanediol, and 10 g of DMS. The weighed solution was mixed with stirring until a homogeneous mixture was obtained. Then 75 g of water was added with stirring.

For further experiments, the photosensitizer was dissolved in each microemulsion to the appropriate concentration and stirred until the photosensitizer was completely dissolved.

B) Contact Angle Test The wettability of the surface by the microemulsion used was measured using a contact angle test.

For the contact angle test, emulsions without the aforementioned photosensitizers and photosensitizers TMPyP, SA-PN-01a, SA-PN-02a, SA-PN-24d, FL-AS-H-1 or A photosensitizer-containing emulsion containing FL-AS-H-2 was used.

In order to compare the new dispersion with conventional alcohol-containing disinfection solutions, aqueous ethanol solutions of various concentrations (10 wt% ethanol to 90 wt% ethanol) were also used as reference solutions.

Furthermore, the diluted solutions of the photosensitizer-free emulsion and the photosensitizer-containing emulsion described above were used to dilute the corresponding microemulsions in five steps until the water content was 99 wt%.

Contact angles were measured using a contact angle measurement device Dataphysics OCA 35 from DataPhysics Instruments GmbH (Filderstadt, Germany) according to the manufacturer's instructions.

For each measurement, 2.5 μl of each solution to be tested was applied to a glass slide as the test surface using an automatic Hamilton syringe at room temperature under full air conditioning (temperature: 25 °C, atmospheric pressure: 1013 mbar, relative humidity: 50%). , was dropped, and images were taken at 1 second time intervals.

Next, in each captured image, both the left and right contact angles between the droplet and the test surface were measured using software SCA 20wof manufactured by DataPhysics Instruments GmbH, and the average value of the measured contact angles was calculated. All measurements were repeated four times each.

FIG. 1 shows the average values of contact angles measured in aqueous ethanol solutions using various concentrations of ethanol (10 wt% ethanol to 80 wt% ethanol).

Furthermore, as an example, the average values of contact angles measured for microemulsions E1 to E4 that do not contain a photosensitizer are shown in FIG.

The average value of the contact angle measured in microemulsions E1 to E4 containing 100 μm of each of the photosensitizers used is the same as the contact angle measured in microemulsions E1 to E4 that do not contain the photosensitizer. It changed only slightly.

The contact angles in various microemulsions containing SDS and TWEEN® 20 were significantly lower compared to pure water. In order to achieve wettability comparable to the glass surfaces used, it appears necessary to use 40 wt% or more of ethanol.

The effect of diluting the microemulsion is shown in Figure 2 when Emulsion E3 (DMS; TWEEN® 20/1,2-pentanediol (1:3); water), which does not contain a photosensitizer, is used. Shown as an example.

As can be seen from FIG. 2, microemulsion E3 can be diluted with approximately 8 times the amount of water in the above-mentioned test without a significant increase in the contact angle due to dilution. Even at a 16-fold dilution, it shows sufficient wetting of the plate glass used in the test.

Microemulsions E1, E2 and E4 and one of the photosensitizers used (TMPyP, SA-PN-01a, SA-PN-02a, SA-PN-24d, FL-AS-H-1a, or FL Similar results were obtained for microemulsions E1 to E4 each containing 5 μM of -AS-H-2).

C) UV/VIS measurement The absorption of the photosensitizers (TMPyP, SA-PN-01a, and FL-AS-H-1a) used in each microemulsion E1 to E4 was measured in the wavelength range of 250 nm to 600 nm. It was measured by recording the absorption spectrum of

In this test, photosensitizers SA-PN-01a and FL-AS-H-1a were dissolved in water and the respective microemulsions E1-E4 to a concentration of 20 μM.

The photosensitizer TMPyP was used at a concentration of 5 μM in each case, since the absorption of dissolved TMPyP was relatively high.

Absorption spectra were measured using a Varian Cary BIO UV/VIS/IR spectrometer (Agilent Technologies Inc., Santa Clara, Canada) using a 10 nm Hellma quartz cuvette (SUPRASIL 101-QS, Hellma GmbH&Co.KG, Mülheim, Germany). , USA).

The measured absorption spectra of TMPyP, SA-PN-01a and FL-AS-H-1a in microemulsions E1 to E4 are similar to those of TMPyP, SA-PN-01a and FL-AS-H-1a in the corresponding water. The absorption spectrum in 1a is almost the same within the error range.

No differences are seen in terms of signal intensity or spectral changes.

D) Measurement of singlet oxygen formed after irradiation

The formation of singlet oxygen after irradiation in photosensitizer-containing microemulsions was measured by time-resolved singlet oxygen fluorescence measurements.

In the measurements corresponding to each case, the photosensitizers used were dissolved to 5 μM in water or in emulsions E1 to E4.

Time-resolved singlet oxygen fluorescence measurements were performed according to the method described in S. Y. Egorov et al. 1999.

In the generation of singlet oxygen, a tunable laser system (model: NT242-SH/SFG, serial number: PGD048, manufactured by Firma EKSPLA, Vilnius, Latvia) was used. The single laser beam generated is directed towards a photodiode and provides a trigger signal for time-correlated single photon counting.

The remaining part of the laser beam was transferred to a 1 cm thick quartz cuvette (SUPRASIL 101-QS, Hellma GmbH & Co. KG, Mülheim, Germany). Into the cuvette was placed the solution to be tested.

Singlet oxygen formation is investigated by direct detection of time-resolved and wavelength-resolved singlet oxygen fluorescence.

Singlet oxygen fluorescence was performed by the method of nitrogen-cooled photomultiplier tube (model R5509-42, Hamamatsu Photonics, Hamamatsu, Japan) and multiscale analysis (7886S, FAST Com Tec GmbH, Oberhaching, Germany). .

Singlet oxygen fluorescence was detected in the wavelength range of 1200 nm to 1400 nm using an intermediate filter placed in front of the photomultiplier tube.

As an example, time-resolved singlet oxygen spectra for each photosensitizer (TMPyP, SA-PN-01a and FL-AS-H-1a) are shown in FIGS. 3 to 5. Figure 3 shows that the photosensitizer TMPyP was measured in water (w), microemulsion E1 (E1) or microemulsion E2 (E2) in the presence of a concentration of photosensitizer TMPyP of 5 μM, respectively. A time-resolved singlet oxygen spectrum is shown. Figure 4 shows the time resolution measured in the presence of photosensitizer SA-PN-01a at a concentration of 5 μM in water (w), microemulsion E1 (E1) or microemulsion E2 (E2), respectively. Singlet oxygen spectrum is shown. Figure 5. Measured in the presence of photosensitizer FL-AS-H-1a at a concentration of 5 μM in water (w), microemulsion E1 (E1) or microemulsion E2 (E2), respectively. Time-resolved singlet oxygen spectrum.

A summary of singlet oxygen detection is shown in Table 1.

Each of the photosensitizers used (TMPyP, SA-PN-01a and FL-AS-H-1a) generated singlet oxygen after irradiation with electromagnetic waves. The quantum yield was calculated using the method described in Baier J. et al. Measured according to

The singlet oxygen formed has a significantly longer half-life in the respective microemulsion compared to water. The half-life of singlet oxygen formed in water is approximately 3.5 μs, whereas the microemulsion increased the half-life of singlet oxygen formed by approximately twice as long. .

The relative yield of singlet oxygen for each photosensitizer relative to the total amount of singlet oxygen formed in water was calculated based on the overall proportion.

The quantum yield of singlet oxygen in microemulsions is at least twice as high as in water.

The formation of singlet oxygen in the microemulsion with FL-AS-H-1a used is increased by 5 times than that in water, and the formation of singlet oxygen in the microemulsion with SA-PN-01a is increased by 5 times than that in water. Formation is increased by a factor of 7 over that in water.

表1：水、マイクロエマルションＥ１（ＤＭＳ；ＳＤＳ／１－ペンタノール（１：２）；水）およびマイクロエマルションＥ２（ＤＭＳ；ＳＤＳ／１，２－ペンタンジオール（１：２）；水）中の光増感剤ＴＭＰｙＰ、ＳＡ－ＰＮ－０１ａおよびＴＭＰｙＰ（それぞれ５μＭ）における一重項酸素測定の結果。

Table 1: In water, microemulsion E1 (DMS; SDS/1-pentanol (1:2); water) and microemulsion E2 (DMS; SDS/1,2-pentanediol (1:2); water) Results of singlet oxygen measurements with photosensitizers TMPyP, SA-PN-01a and TMPyP (5 μM each).

In summary, it can be said that the use of microemulsions has a positive influence on the optophysical properties of the photosensitizers used.

In one of the microemulsions used, a significantly higher amount of singlet oxygen was formed. Moreover, the light absorption of each photosensitizer used in the microemulsion was maintained substantially unchanged.

E) Phototoxicity Measurement To examine the phototoxicity of the microemulsion according to the present invention, an MTT assay was used.

Detection of cell survival by MTT assay was performed using a yellow water-soluble dye, 3-(4,5-dimethylthiazole- Based on the reduction of 2-yl)-2,5-diphenyltetrazolium bromide (MTT, Sigma-Aldrich Chemie GmbH, Munich, Germany). MTT is a membrane-permeable dye that is metabolized by mitochondrial dehydrogenases in living cells, forming formazan crystals as the end product.

Formazan crystals are not membrane permeable and accumulate in intact, proliferating cells. After cell lysis and solubilization of the crystals, the dye is quantified by colorimetric measurement at 550 nm in a multilayer spectrophotometer. The amount of formazan formed is recorded as absorbance (OD value). Since the measured amount of formazan is directly proportional to the number of proliferating cells, this test is suitable for determining the phototoxicity of the microemulsions used. Cell numbers were assigned to measured OD values based on a previously generated standard curve.

The respective photosensitizers TMPyP, SA-PN-01a, SA-PN-02a, SA-PN-24d, Fl-AS-H-1a, or FL-AS-H-2 in microemulsions E1 to E4 The concentrations were 0 μM, 10 μM, 25 μM, 50 μM, 100 μM, 250 and 500 μM.

In addition, each microemulsion E1-E4 without photosensitizer was used as a control.

Phototoxicity measurements were performed in Escherichia coli (E. coli; ATCC number: 25922) and Staphylococcus aureus (S. aureus; ATCC number: 25923) using Mosmann (1083) (Mosmann T.: Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. in: J. Immunol. Methods. 1983 (65); pages 55-63).

25 μl of an overnight culture suspension (absorbance at 600 nm: 0.6) of the bacteria used in Muller-Hinton liquid medium (Merck KGaA, Darmstadt, Germany) was added to a 96-well microtiter plate along with 25 μl of the test solution. (Cellstar, Greiner Bio-One, Frickenhausen, Germany) for 10 seconds at room temperature in the dark.

The microtiter plate was then irradiated for 40 seconds. For irradiation, a blue light source called BlueV from Waldmann (Villingen-Schwenningen, Germany) was used. Here, a light beam of 380 to 480 nm is irradiated (maximum irradiation: about 420 nm). The applied voltage was 20 mW/ ^cm2 .

Each test was accompanied by three control substances to avoid implicating side effects of irradiation/photosensitizer (PS) on bacterial survival: (i) no PS, light only (=photocontrol substance); ii) no light, only PS (=shading control), and (iii) no light or PD (=reference control).

After the irradiation was completed, 75 μl of 25 wt% SDS solution was added to each well of the microtiter plate. The bacterial cells were then lysed overnight at 37°C in an incubator.

Finally, the absorbance (OD) at 550 nm was measured using a microtiter plate photometer (model EAR 400 AT, SLT Laborinstruments Austria, Salzburg, Austria).

After cell lysis and solubilization of the crystals, the dye can be subsequently quantified by colorimetric measurement at 550 nm in a multilayer spectrophotometer (ELISA reader).

Colony forming units (CFU) were measured using the method published by Miles and Misra (Miles, AA; Misra, SS, Irwin, JO (1938 Nov). "The estimation of the bactericidal power of the blood" The Journal of hygiene 38 (6): 732-49). Finally, serial dilutions of the corresponding cell suspensions from 10 ⁻² to 10 ⁻⁹ times were performed. 3×20 μl of the corresponding bacterial dilutions were each dropped onto Mueller-Hinton plates and incubated at 37° C. for 24 hours. The number of surviving colony forming units (KBF or CFU) was then determined. All experiments were repeated three times each.

In water and in any one of the microemulsions E1 to E4 in the photosensitizer TMPyP at a concentration range of 10 μM to 100 μM, E. coli and S. aureus are destroyed by the singlet oxygen formed during irradiation. Ta.

At concentrations of photosensitizer TMPyP higher than 100 μM in water, a shielding effect occurs. TMPyP can absorb 25-30 times more light. Therefore, the formation of singlet oxygen at high concentrations above 100 μM was reduced, and accordingly, the concentrated aqueous solution was able to reduce the number of E. coli and S. aureus by about 2 log ₁₀ .

In contrast, when using TMPyP in any one of the microemulsions E1 to E4, the resulting shielding effect is significantly lower. Therefore, the amount of singlet oxygen formed at high concentrations of TMPyP (higher than 100 μM to 500 μM) is high compared to aqueous solutions.

As a result, concentrated microemulsions with TMPyP at concentrations higher than 100 μM to 500 μM were only able to reduce the number of E. coli and S. aureus by as much as 5 log ₁₀ .

Photosensitizers SA-PN-01a, SA-PN-02a and SA-PN-24d are more effective against E. coli and S. aureus when used in microemulsions than when used in water. , was more effective.

When using SA-PN-01a, SA-PN-02a and SA-PN-24d in the concentration range of 50-500 μM, S. aureus was completely destroyed (greater than 6 log ₁₀ , the number decreased after irradiation). ) was done.

When SA-PN-01a is used in any one of the microemulsions E1 to E4, SA-PN-01a at a concentration of 25 μM results in more than 6 log ₁₀ of E. coli and S. aureus after irradiation. It may be possible to reduce the number.

Furthermore, a concentration of 10 μM of SA-PN-01a in any one of microemulsions E1-E4 is sufficient to reduce the number of E. coli and S. aureus by as much as 3 log ₁₀ after irradiation.

In Figures 6a and 6b, the effect of SA-PN-01a in water or in microemulsion E2 (E2) on Staphylococcus aureus is shown as an example.

Figure 6a shows the effect of an aqueous solution of photosensitizer SA-PN-01a at the indicated concentrations on Staphylococcus aureus after irradiation with a BlueV light source (irradiation time: 40 seconds). (Dotted bars) The applied voltage was 20 mW/cm in each case.

As a control, Staphylococcus aureus was treated with pure water without SA-PN-01a (concentration: 0 μM) and with SA-PN-01a in water (concentration: 500 μM). Two unirradiated samples (black bars) were prepared.

Figure 6b shows by way of example the effect of the photosensitizer SA-PN-01a in microemulsion E2 at the indicated concentrations on Staphylococcus aureus after irradiation with a BlueV light source (irradiation time: 40 seconds). (Dotted bars) The applied voltage was 20 mW/cm in each case.

When Staphylococcus aureus was treated with microemulsion E2 (concentration: 0 μM) that did not contain SA-PN-01a, and when it was treated with SA-PN-01a (concentration: 500 μM) in microemulsion E2, Two unirradiated samples (black bars) were prepared as controls.

The colony-forming units of viable bacteria, expressed as colony-forming units per mL (CFU/mL), are shown in each case, determined according to a test according to the method published by Miles and Misra.

For the photosensitizer FL-AS-H-1a, FL-AS-H1a at a concentration of 10 μM in any one of microemulsions E1-E4 reduced E. coli and S. aureus by about 2 log ₁₀ . It was measured that

Example 2:
A) Preparation of various oil-containing microemulsions Additionally, oil-containing microemulsions E5 and E6 were prepared.
The wt% of the components of microemulsions E5 and E6 shown below are each based on the total weight of the respective microemulsion without photosensitizer.

Microemulsion E5:
66wt% Dodecane 29wt% Lutensol AO7
5wt% water

Microemulsion E6:
66wt% paraffin oil 4wt% water 10wt% Lutensol AO7
20wt% Costellan SQ/OVH

The surfactant Lutensol AO7 is commercially available from BASF SE (Ludwigshafen, DE). Lutensol AO7 is an ethoxylated mixture of fatty alcohols with 13 to 15 carbon atoms, with an average of 7 ethyl oxides (PEG7).

The surfactant Costellan SQ/OVH is commercially available from Dr. W. Kolb AG (Hedingen, CH). Costellan SQ/OVH is a sorbitan oleate ester with an average of 1.5 oleic acid molecules per molecule (sorbitan oleate).

B) UV/VIS measurement The absorption spectrum of the photosensitizer FL-AS-H-1a used in each microemulsion E5 and E6 was measured in the wavelength range of 230 nm to 600 nm as described in Example 1. It was measured by recording. Here, photosensitizer FL-AS-H-2 was dissolved in microemulsions E5 and E6 and water to a concentration of 10 μM.

The absorption spectrum of FL-AS-H-2 in microemulsion E6 shows no changes compared to the spectrum measured in water. Only the absorption signal intensity is higher than in water or microemulsion 5.

Furthermore, the absorption spectra of FL-AS-H-2 in microemulsions E5 and E6 were identical to those in water measured after irradiation with different light doses.

For irradiation, a Waldmann BlueV light source emitting light at 380-480 nm was used (maximum emission: approximately 420 nm). The applied light dose was between 5.5J and 990J.

Photosensitizer FL-AS-H-2 was reduced both in water and in microemulsions E5 and E6. The reduction in water was significantly faster than that in microemulsions E5 or E6.

Example 3
A) Preparation of Gels Containing Photosensitizers The wt% of the components of gels G1-G3 shown below are each based on the total weight of the gel used.

Gel G1: (Comparative example - no surfactant)
Ingredients/amount [mL]
Carbopol SF-1 (4wt% aqueous solution)/6.25
Sodium hydroxide (2wt% aqueous solution)/2
Sodium chloride (10wt% aqueous solution/4
Carbopol hydrate SF-1 polymer, an acrylic copolymer, was purchased from Lubrizol Corporation (Wickliffe, OH, USA) and used as a gelling agent.

Gel G2:
Ingredient amount [mL]
Carbopol SF-1 (4wt% aqueous solution) 6.25
Sodium hydroxide (2wt% aqueous solution) 2
Sodium chloride (20wt% aqueous solution) 2
Brij35 (6wt% aqueous solution) 2
Brij35, polyoxyethylene (23) lauryl ether, was obtained from Merck KGaA (Darmstadt, Del.) and was used as a surfactant.

Gel G3:
Component Amount Carbopol SF-1 (4wt% aqueous solution) 6.25
Sodium hydroxide (2wt% aqueous solution) 2
Sodium chloride (20wt% aqueous solution) 2
PLANTACARE 818 UP (6wt% aqueous solution) 2
PLANTACARE 818 UP, a C8-C17 fatty alcohol glucoside D-glucopyranose, was purchased from BASF SE (Ludwigshafen, DE) and used as a surfactant.

According to the specifications in the manufacturer's instructions, the surfactant has a length distribution of fatty alcohols including:
C6 maximum 0.5%
C8 24-30%
C10 15-22%
C12 37-42%
C14 12-18%
C16 maximum 4%

First, the above-mentioned amount of 2 wt% NaOH aqueous solution was added at once to the corresponding amount of 4 wt% Carbopol hydrated SF-1 aqueous solution in a measuring cup with stirring. After a clear gel was formed, the above amount of sodium chloride solution was added to adjust the viscosity.

Subsequently, each of the above-mentioned amounts of a 6 wt % aqueous solution containing any one of the above-mentioned surfactants was added dropwise with stirring.

The used light exchanger TMPyP was added to each gel to a final concentration of 100 μM.

The G1, G2 and G3 gels with photosensitizer TMPyP and the G1, G2 and G3 gels without photosensitizer TMPyP were transparent and exhibited pseudoelastic properties.

Furthermore, in gels G2 and G3, the density did not change during storage at 50°C and 0°C for 24 hours.

B) Contact Angle Test The surface wettability of the prepared gel was measured by a contact angle test.

In contact angle tests, the gels described above were used as gels without photosensitizer and gels with photosensitizer.

Contact angle testing was performed as described in Example 1. A polyethylene test plate was used here as the test surface.

The measured contact angles of photosensitizer-free gels G2 and G3 with the addition of corresponding amounts of the surfactants indicated above are shown by way of example in FIG. 7. The measured contact angles of each of the photosensitizer containing gels G2 and G3 are identical.

The measurements showed that the lowest contact angle, ie the highest wettability, is achieved at a proportion of 0.5 wt%, based on the total weight of the gel.

To enable the dissolution of the bacterial aggregates present, the proportion of surfactant was subsequently increased to 1.0 wt% relative to the total weight of the gel.

C) UV/VIS measurement Record the absorption spectra of each of the gels G1 to G3 and the photosensitizer TMPyP used in water in the wavelength range of 250 nm to 600 nm as described in Example 1. It was measured with

The photosensitizer TMPyP was dissolved in gels G1 to G3 and in water to a concentration of 10 μM.

The absorption spectra of TMPyP in gels G1-G3 showed no change compared to the spectra measured in water.

D) Measurement of singlet oxygen formed after irradiation The formation of singlet oxygen after irradiation in microemulsions containing photosensitizers was measured using time-resolved singlet oxygen fluorescence measurements as described in Example 1. It was measured using

Singlet oxygen formation was also detectable in the presence of TMPyP (final concentration: 10 μM) in gels G1, G2 and G3 after irradiation.

In FIG. 8, a time-resolved singlet oxygen spectrum of photosensitizer TMPyP in gel G3 is shown as an example. The signal rise time (t _R ) was 2.7 μsec.

The measured signal decay time ( _tD ) was 7.4 μsec.

In FIG. 9, a wavelength-resolved singlet oxygen spectrum of photosensitizer TMPyP in gel G3 is shown as an example.

A prominent peak in the wavelength-resolved spectrum at 1270 nm clearly indicates that singlet oxygen was formed by TMPyP in the gel after irradiation.

The decay time of the singlet oxygen signal measured in gel (7.4 μsec) is significantly longer compared to the decay time of the singlet oxygen signal measured in water (~3.5 μsec). Therefore, the singlet oxygen formed in any one of the gels G1-G3 tested is more effective for a longer period of time.

Literature:
Butenandt J., Epple R., Wallenborn E.-U., Eker APM, Gramlich V. und Carell T.: A comparative repair study of thymine- and uracil-photodimers with model compounds and a photolyase repair enzyme, Chem. Eur. J. 2000, Vol. 6, No. 1, pages 62 - 72,
Svoboda J., Schmaderer H. und Konig B.: Thiourea-enhanced flavin photooxidation of benzyl alcohol; Chem. Eur. J. 2008, 14, pages 1854 - 1865
Egorov SY, Krasnovsky AA, Bashtanov MY, Mironov EA, Ludnikova TA und Kritsky MS; Photosensitization of singlet oxygen formation by pterins and flavins. Time-resolved studies of oxygen phosphorescence under laser excitation. Biochemistry (Mosc)1999, 64 (10), p 1117 - 1121.

Claims (24)

A dispersion,
(a) at least one photosensitizer which is phenalenone and/or a derivative thereof, wherein the derivative of phenalenone is selected from compounds having the following formulas (2) to (28), and mixtures thereof; selected from the group),
(b) at least one liquid polar phase; and (c) at least one surfactant;
Dispersion, wherein said dispersion is in the form of a microemulsion, a gel or a mixture thereof at a temperature in the range from 2 to 50°C and a pressure in the range from 800 to 1200 mbar.

2. The dispersion of claim 1, wherein the at least one liquid polar phase comprises at least one polar solvent. 3. Dispersion according to claim 2, wherein the at least one polar solvent is water. 4. The method of claim 1, wherein said at least one surfactant is selected from the group consisting of nonionic surfactants, anionic surfactants, cationic surfactants, amphoteric surfactants and mixtures thereof. Dispersion according to any one of the above. 5. The dispersion of claim 4, wherein the at least one surfactant is selected from the group consisting of nonionic surfactants, anionic surfactants and mixtures thereof. Dispersion according to claim 4 or 5, wherein the cationic surfactant is selected from the group consisting of quaternary alkylammonium salts, esterquats, acylated polyamines, benzylammonium salts or mixtures thereof. Nonionic surfactants include polyalkylene glycol ether, alkyl glucoside,
Dispersion according to any one of claims 4 to 6, selected from the group consisting of alkyl polyglycosides, alkyl glycoside esters and mixtures thereof. The anionic surfactant is selected from the group consisting of alkyl carboxylates, alkyl sulfonates, alkyl sulfates, alkyl phosphates, alkyl polyglycol ether sulfates, sulfonates of alkyl carboxylates, N-alkyl sarcosinates, and mixtures thereof. , the dispersion according to any one of claims 4 to 7. 9. According to any one of claims 1 to 8, the dispersion further comprises at least one liquid non-polar phase, said at least one liquid non-polar phase comprising at least one non-polar solvent. Dispersions as described. The at least one non-polar solvent is an alkane having 6 to 30 carbon atoms, a monocarboxylic acid ester having 4 to 20 carbon atoms, or a polycarboxylic acid having 6 to 20 carbon atoms. 10. The dispersion of claim 9 selected from the group consisting of acid esters, and mixtures thereof. Dispersion according to any one of claims 1 to 10, wherein the dispersion further comprises at least one alkanol having 1 to 6 OH groups and having 2 to 12 carbon atoms. thing. Dispersion according to any one of claims 1 to 11, wherein the dispersion at a pressure in the range from 800 to 1200 mbar and a temperature in the range from 2 to 50° C. comprises or is a microemulsion. thing. 13. Dispersion according to claim 12, wherein the microemulsion has droplets having a droplet size of less than 1 μm. Dispersion according to claim 12 or 13, wherein the microemulsion is an O/W microemulsion, a water-in-oil (W/O) microemulsion or a bicontinuous microemulsion. According to any one of claims 1 to 8, the dispersion further comprises at least one pH adjusting substance, which is an inorganic acid, an organic acid, an inorganic base, an organic base, a salt thereof or a mixture thereof. Dispersions as described. 12. The dispersion further comprises at least one gelling agent selected from the group consisting of carboxyvinyl polymers, polyacrylamides, polyvinyl alcohols, acylated polyethylene amines, alginates, cellulose ethers, and mixtures thereof. The dispersion according to any one of 1 to 8 or 15. 17. The dispersion according to any one of claims 1 to 8, 15 or 16, wherein the dispersion at a pressure in the range from 800 to 1200 mbar and a temperature in the range from 2 to 50°C comprises or is a gel. dispersion of. For the photodynamic inactivation of microorganisms selected from the group consisting of viruses, archaea, bacteria, bacterial spores, fungi, fungal spores, protozoa, algae, and blood-borne parasites. Use (other than therapeutic use within the human body) of the dispersion according to any one of Item 17. 19. Use according to claim 18 for surface cleaning and/or surface coating of objects. For surface cleaning and/or surface coating of medical products, food packaging, food, beverage packaging, beverage containers, textile products, building materials, electronic equipment, household equipment, furniture, windows, floors, walls or sanitary products, Use according to claim 18 or 19. Use according to claim 18 for sterilization of liquids. A method for the photodynamic inactivation of microorganisms, including viruses, archaea, bacteria, bacterial spores, fungi, fungal spores, protozoa, algae, blood-borne parasites or combinations thereof, comprising: The method includes the following steps:
(A) contacting said microorganism with at least one dispersion according to any one of claims 1 to 17; and (B) applying electromagnetic radiation of a suitable frequency and energy density to said microorganism and said microorganism. A method (other than a therapeutic method within a human body) comprising the step of irradiating at least one photosensitizer contained in a dispersion. For use in photodynamic therapy for the inactivation of microorganisms selected from the group consisting of viruses, archaea, bacteria, bacterial spores, fungi, fungal spores, protozoa, algae, and blood-borne parasites. , the dispersion according to any one of claims 1 to 17. Dispersion according to any one of claims 1 to 17 for use according to claim 23 in the treatment and/or prevention of diseases of dental tissues and/or gums.

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